Cancer prevalence after exposure to Wnt-activating drugs: a systematic review
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* Ahmed Alkashaf
* Natalia Smith-Cortinez
* Georgina E Fenton
* Sebastian Thomas Bok
* Robert J Stokroos
* Inge Stegeman
* Louise V Straatman

## Abstract

**Objectives** To assess whether treatment with drugs that activate the Wnt pathway leads to an increased risk of cancer.

**Design** Systematic review reported using Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) reporting guidelines.

**Data sources** PubMed, Embase and the Cochrane Library were searched through 1 November 2024.

**Eligibility criteria** All primary research articles reporting clinical studies, including observational and experimental studies, were included in this review. All studies were eligible for inclusion if they included the exposure of interest, that is, compounds which have been described to activate the Wnt pathway, and the outcome of interest, that is, cancer prevalence. No language restrictions were performed.

**Data extraction and synthesis** This study was reported according to the PRISMA reporting guidelines. The search string, objectives, and study protocol methods were defined before the study was initiated.

**Results** A total of 48 studies investigating drugs that activate the Wnt pathway (valproic acid, lithium, cimetidine, olanzapine, clozapine, haloperidol) were included in this systematic review. The results from this systematic review show that, at least for the included compounds in the currently used systemic dosage, cancer prevalence does not significantly increase.

**Conclusions** The current study found that the use of drugs that activate the Wnt pathway was not associated with an increased risk of cancer. As a promising agent in the regenerative therapy field, further research into Wnt activation as a treatment option should be explored.

**PROSPERO registration number** CRD42021286193.

*   Prevalence
*   Epidemiology
*   ONCOLOGY

### STRENGTHS AND LIMITATIONS OF THIS STUDY

*   Inclusion of all study designs, providing a broad overview of studies covering the topic.

*   Substantial heterogeneity in study designs, inclusion of types of patients and conditions.

*   We cannot generalise the outcomes based on the broad mechanism of action of the compounds included.

## Introduction

The Wnt/β-catenin pathway is a signalling cascade that controls cell proliferation, cell polarity and cell fate determination during embryonic development and tissue homeostasis.1 Wnt/β-catenin signalling is known to be involved in the development of multiple tissues, including brain, eye, ear, spinal cord, bone and cartilage among many others.2 In adulthood, crucial roles in the function of intestine, bone and skin have been described for Wnt/β-catenin signalling.2 Wnts (the ligands that activate the Wnt/β-catenin signalling pathway) are growth stimulatory factors that ultimately lead to cell proliferation. Importantly, dysregulated Wnt signalling has been associated with several diseases such as degenerative diseases,1 neurodegenerative disorders,3–5 schizophrenia,5 ageing-related tissue fibrosis,6 autoimmune diseases7 and many types of cancer.8–12

Currently, targeting the Wnt/β-catenin signalling pathway, either by activating or inhibiting it, is being researched as therapy for some types of cancer,13 14 neurodegenerative diseases15–18 and hair loss.19 20 When therapeutic agents target crucial developmental signalling pathways (such as Wnt, Notch, Hedgehog and bone morphogenic protein pathways) serious and devastating effects on embryogenesis and carcinogenesis might arise due to increased cell proliferation. In line with this, continued activation of the Wnt pathway has been associated with therapy resistance in patients with cancer and has been shown to promote self-renewal of cancer cells.21 Unfortunately, the effect of Wnt activation on cancer prevalence has not been consistently studied. In the last 15 years, common drugs used in the clinic have been described to activate the Wnt pathway.22 23 The most common Wnt activators used in the clinic are lithium and valproic acid (VPA), which have been used as treatment for psychiatric disorders since the 1960s.24–26 Besides, many novel therapeutic drugs have been synthesised specifically to activate Wnt in the last 10 years and are used in the clinic.27 Many of these drugs activate the Wnt signalling pathway through the inhibition of glycogen synthase kinase 3 (GSK3).28 This is one of the most well-studied mechanisms for activating the Wnt signalling pathway.28

There are many novel therapeutic drugs in development for clinical usage that activate the Wnt pathway. However, safety concerns regarding its activation remain.29 Therefore, we conducted a systematic review to address the association between the use of drugs that activate the Wnt pathway and the prevalence of any type of malignancy in the clinic. Our aim was to assess whether treatment with drugs that activate Wnt leads to an increased risk of cancer.

## Methods

We evaluated all data available on clinical use of Wnt activators following the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) 2020 writing guideline for systematic reviews.30 Patient, Intervention, Compariron, and Outcome (PICO) framework was used to improve the search strategy.31 The outcome of interest was the prevalence of any cancer, malignancy or neoplasm, regardless of age, sex and geographical location. The exposure of interest was any compound activating the Wnt pathway, regardless of indication, dosage and duration. An overview of the included compounds and their mechanism of action is available in table 1.

View this table:
[Table 1](http://bmjopen.bmj.com/content/15/5/e103296/T1)

Table 1 
Mechanisms of action of all drugs included

### Search strategy

The final search was done on 1 November 2024. PubMed, Embase and Cochrane databases were searched. All articles until 1 November 2024 were included in the search. On Embase, conference abstracts and reviews were removed. No further search filters were used. No language restrictions were applied. The search syntax consisted of names of medication with known Wnt activating properties used in the clinic combined with synonyms for ‘cancer’. The full search strategy can be found in online supplemental table S1.

### Supplementary data

[[bmjopen-2025-103296supp001.pdf]](pending:yes)

### Article selection

All primary research articles reporting clinical studies, including observational and experimental studies, were included in this review. Studies were eligible for inclusion if they included the exposure of interest, that is, compounds which have been described to activate the Wnt pathway, and the outcome of interest, that is, cancer prevalence. Patients of all ages were eligible for this study. No control group was required. Articles assessing compounds with no clear Wnt activating properties were excluded. Animal studies, in vitro studies and non-primary research articles like review articles and letters were excluded. Two independent reviewers (AA, GF, NS-C, STB) screened titles and abstracts of collected studies after duplicate removal for eligibility criteria. Discrepancies were resolved by discussion between the two reviewers until a consensus was reached. Full-text screening was performed by two independent reviewers, and disagreements were solved as above. Rayyan systematic review tool32 was used to semi-automate the primary screening.

### Data extraction

A data extraction table was used to extract study characteristics and findings by two reviewers (AA and NS-C) with the software Microsoft Excel. Data extraction was performed by one reviewer and checked by another reviewer. Discrepancies were solved by discussion between the two reviewers until a consensus was reached. The data extraction table included the following information: Study, indication for intervention, population, age, geographical location, used Wnt activator, used control group, cancer prevalence and cancer type (online supplemental tables S2–S10). No authors were contacted due to data unavailability after inclusion.

### Supplementary data

[[bmjopen-2025-103296supp002.pdf]](pending:yes)

### Supplementary data

[[bmjopen-2025-103296supp003.pdf]](pending:yes)

### Critical appraisal

The methodological quality of included articles was assessed by two reviewers (AA and NS-C) using the Newcastle-Ottawa Scale (NOS) for non-randomised studies as a reference guide.33 Risk of bias assessment was performed by one reviewer and checked by another reviewer. Risk of bias in cohort studies was assessed for the following domains: selection bias, comparability of cohorts and outcome (online supplemental tables S11–S18).

### Effect measures

Results were expressed according to the reported ratios from the published studies. This includes percentages, ORs, risk ratios (RR) and HRs, in accordance with study design and available data. When unavailable, RRs and ORs were calculated. All ratios were used to answer the main questions qualitatively. No quantitative analyses were conducted for this systematic review.

### Study registration

PROSPERO, CRD42021286193.

### Patient and public involvement

None.

## Results

### Article selection

Our PubMed database search until November 2023 yielded a total of 25 969 articles. After duplicate removal, 20 427 articles remained, which were screened for title and abstract. Following title and abstract screening, 172 articles were eligible for full-text screening. All 172 articles could be retrieved. After full-text screening, 48 studies were included for this review. Main reasons for exclusion were outcome that was not in our inclusion criteria, publication type, study design, population and different drug. Article screening is summarised in the flowchart in figure 1.

![Figure 1](http://bmjopen.bmj.com/https://bmjopen.bmj.com/content/bmjopen/15/5/e103296/F1.medium.gif)

[Figure 1](http://bmjopen.bmj.com/content/15/5/e103296/F1)

Figure 1 
Article selection flow diagram. The identification of studies via databases and registers is presented above. The selection was divided into three stages. Identification in databases and registers. Then screening and lastly inclusion. The protocol was performed based on the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) 2020 flow diagram for new systematic reviews which included searches of databases and registers only.

### Study characteristics

Included studies, which are summarised in online supplemental tables S2–S10, consisted of 21 cohort, 19 case–control and 8 pharmacovigilance studies. Drugs with reported Wnt activating properties included were VPA (13 studies), lithium (15 studies), haloperidol (7 studies), cimetidine (10 studies), clozapine (9 studies) and olanzapine (7 studies). Some studies assessed multiple drugs of interest.

Studies were performed in multiple countries, including multiple European and Asian countries in addition to the USA. Additionally, a WHO pharmacovigilance database consisting of 160 countries was included.34 Most common indications were psychotropic, gastrointestinal and neurological use. All compounds were administered systemically in clinical dosing. Most studies assessed any type of cancer prevalence. All studies assessed cancer risk by analysing clinical data or performing questionnaires. In addition, a few studies included histological verification for cancer diagnosis in addition to clinical data.35–38 All Wnt activating compounds were used in their clinical dose respective to their indication.

### Risk of bias

Based on the NOS, all but one included study concerning VPA were determined to have a low risk of bias (online supplemental tables S11 and–S12). One study by Stritzelberger *et al* (online supplemental table S12) did not show all data concerning VPA.39

Concerning lithium, for both cohort and case–control studies, most studies were determined to have low risk of bias (online supplemental tables S13 and S14). One cohort study by Zaidan *et al* (online supplemental table S13) and three case–control studies by Hallas *et al*, Kahan *et al* and Tamim *et al* (online supplemental table S14) were subject to a high risk of bias.40–43

Most studies reporting cimetidine use had a high risk of bias (online supplemental tables S15 and S16). Main points were missing data, lack of control group or no comparability of groups. The cohort study by Velicer *et al* (online supplemental table S15) was determined to be of fair risk of bias.44 Only the study by Rossing *et al* (online supplemental table S15) was determined to be of low risk of bias.45

For haloperidol, both the cohort study by Wang *et al* (online supplemental table S17) and the case–control study by Friedman *et al* (online supplemental table S18) were determined to have low risk of bias.46 47 The risk of bias in the case–control study by Hsieh *et al* (online supplemental table S18) was high because they used non-gastric cancers as a control for gastric cancer instead of healthy individuals with no cancer.48 The case–control study by Pottegård *et al* (online supplemental table S18) was determined to be of good quality.37

### Outcomes

#### VPA

Seven cohort studies assessed the association between VPA use and cancer prevalence.35 49–54 Six studies showed no statistically significant difference in cancer prevalence between exposed versus controlled subjects, respectively (50, RR=0.877 (0.642–1.032); 51, RR=1.18 (0.96–1.46); 52, RR=0.848 (0.563–1.277); 54, RR=0.848 (0.563–1.277); 35, HR=0.96 (0.84–1.19), 1.0 (0.8–1.3), 1.0 (0.7–1.3); 53 RR=1 (0.7–1.3)). The study by Chavez *et al* evaluated melanoma prevalence in VPA-exposed individuals. In this study, VPA-exposed individuals had a significantly reduced prevalence of melanoma compared with controls (49, HR=0.64 (0.51–0.79)).

Additionally, six case–control studies assessed the association between VPA use and cancer prevalence.38 39 43 55–57 All studies showed no statistically significant increase in cancer prevalence between exposed vs controlled subjects, respectively (58, OR=0.85, (0.70–1.04); 43, OR=1.21 (0.95–1.56); 39, p=0760; 55, OR=0.62 (0.42–0.92); 38, 0.2% cases and 0.2% control group; 57, OR=0.58 (0.39–0.56)).

##### Lithium

Nine cohort studies assessed the association between lithium use and cancer prevalence, including melanoma, urinary tract tumours, malignant neoplasms, invasive breast cancer and any type of cancer.36 42 52 53 58–62 Six studies showed no statistically significant difference in cancer prevalence between exposed versus controlled subjects, respectively (36, OR=1.19 (0.71–2.01); 60, RR=1.01 (0.97–1.05); 62, risk difference = −2.8% (−9.7% to 4.1%) for cohort 1 compared with −3.0% (−6.0% to 0.1%) for cohort 2; 61, RR=1.04 (0.89–1.23); 58, RR=0.92 (0.58–1.46); 53, RR=1 (0.6–1.6)). Asgari *et al* and Huang *et al* evaluated cancer risk in lithium-exposed individuals compared with controls. In both studies, lithium-exposed individuals had a significantly reduced cancer risk compared with controls (59, unadjusted HR=0.68 (0.51–0.90); 52, RR=0.426 (0.186–0.975)). Zaidan *et al* found an increased risk of renal tumours in patients exposed to over 20 years of lithium in comparison to both the general population and to kidney function matched controls (based on glomerular filtration rate), p=0.04.42

Additionally, six case–control studies assessed the association between lithium use and cancer prevalence.40 41 43 57 63 64 Five studies showed no statistically significant difference in cancer prevalence between exposed versus controlled subjects, respectively (41, 0.8% vs 0.9% incidence; 64, OR=1.01 (0.86–1.19) for any use, OR=1.06 (0.84–1.34) for>5 years use; 40, standardised incidence ratio=0.93 (0.6–1.38) for male subjects and 1.25 (0.91–1.69) for female subjects; 63, OR=1.3 (0.7–2.1); 57, OR=0.81 (0.58–1.12)). Hallas *et al* showed a slight increase in cancer prevalence in subjects with long-term exposure to lithium,43 OR=1.19 (1.03–1.39)).

#### Cimetidine

Three cohort studies assessed the association between cimetidine use and cancer prevalence.44 65 66 The study by Møller *et al* did not include a control group.65 The remaining two cohort studies investigated gastrointestinal, breast and prostate cancer risk and found no significant increase in cancer risk in the groups exposed to cimetidine in comparison to controls (44, RR=0.97 (0.61–1.53); 66, RR=0.9 (0.8–1.1) for breast cancer risk in women and RR=0.7 (0.6–0.8) for prostate cancer in men)). Rossing *et al* found a slightly increased risk of prostate cancer in a subgroup of men who had filled>21 prescriptions of cimetidine,66 RR=1.4 (1.0–1.9)).

Five case–control studies assessed the association between cimetidine use and cancer prevalence.67–71 In all studies, cimetidine exposed individuals showed no significant difference in ratio compared with controls (67, OR=0.9 (0.6–1.2); 68, OR=0.39 (0.17–0.89); 71, ductal carcinoma, ever use: OR=1.1 (0.8–1.5); >2 years use, 0.9 (0.5–1.5); 70, no analysis reported; 69, OR=2.1 (0.7–6.3)). Lastly, a cohort study and a surveillance study conducted by Colin-Jones *et al* showed no increased cancer prevalence after cimetidine exposure.72 73

#### Haloperidol

A cohort study by Wang *et al* assessed the association between haloperidol use and breast cancer prevalence, including a total of 46 269 women. A breast cancer prevalence of 0.052% (1228 cases in 237 242 person-years in the control group and 240 cases in 46 269 person years in the haloperidol group) was found in both exposed and unexposed groups, indicating no significant increase in breast cancer prevalence in women exposed to haloperidol compared with unexposed women.46

Additionally, three case–control studies assessed the association between haloperidol use and cancer prevalence. A case–control study by Friedman *et al* found a potential negative association between haloperidol use and prostate cancer risk, compared with controls depending on duration,47 at>2 years of use, OR=0.54 (0.20–1.44), at>1 year of use, OR=0.32 (0.12–0.84); at <1 year of use, OR=0.69 (0.48–0.99). Another case–control study by Hsieh *et al* found a reduced risk of gastric cancer associated with haloperidol use,48 OR=0.25 (0.14–0.46). A third, population-based case–control study by Chen *et al* assessed the risk of endometrial cancer after exposure to haloperidol and other antipsychotics. For haloperidol, an increase in endometrial cancer after exposure to haloperidol was found,74 OR=1.75 (1.31–2.34).

Three database studies assessed the association between haloperidol use and cancer prevalence. The database study by Maeshima *et al* using the Japanese adverse drug event database showed no increased risk of breast cancer in women exposed to haloperidol,75 reporting OR (ROR)=0.49 (0.07–3.51). However, the study by Lertxundi *et al* using the European pharmacovigilance database showed a possible increased risk of pituitary tumours of subjects exposed to haloperidol,76 Proportional Reporting Ratio (PRR)=7.0 (4.35–11.3). Finally, a pharmacovigilance study using the adverse event reporting database from the US Food and Drug Administration by Szarfman *et al* suggested a possible increased risk of pituitary tumours in patients exposed to haloperidol,77 Absolute Risk Reduction (ARR)=5.6 (2.9–13).

##### Olanzapine

Three case–control studies assessed the association between olanzapine use and cancer prevalence. A nationwide case–control study by Pottegård *et al* assessed the association between olanzapine use and breast cancer prevalence. Breast cancer cases were verified by histology. This study found a slightly increased risk of oestrogen receptor-positive breast cancer in subjects exposed to olanzapine, attributed to its prolactin-elevating properties when the study was only adjusted for age and gender,37 adjusted OR (aOR)=1.30; 95% CI=1.09 to 1.56); however, in the fully adjusted model, no significant increase was found (aOR=1.15; 95% CI=0.9 to 1.47). Another case–control study by Hsieh *et al* found a reduced risk of gastric cancer associated with olanzapine use48 (OR=0.13 (0.05–0.35)). Lastly, the case–control study by Chen *et al* found no increased risk of endometrial cancer after exposure to olanzapine74 (OR=1.14 (0.56–2.30)).

Three database studies assessed the association between olanzapine exposure and cancer prevalence.75–77 The database study by Maeshima *et al* showed no increased risk of breast cancer in women exposed to olanzapine75 (ROR=0.51 (0.07–3.51)). However, the database studies performed by Lertxundi *et al* and Szarfman *et al* suggested an increased risk of pituitary tumours of subjects exposed to olanzapine76 (PRR=2.53, (1.57–4.1))77; ARR=2.3 (1.4–3.7)).

#### Clozapine

One cohort study by Tiihonen *et al* assessed the risk of developing haematological malignancies after exposure to clozapine. A significant, dose-dependent, increased risk of haematological malignancies was found78 (aOR=3.35 (2.22–5.05) for>5000 defined daily dose cumulative exposure). Four case–control studies assessed the association between clozapine exposure and cancer prevalence. The case–control study by Hsieh *et al* assessed the association between clozapine exposure and cancer prevalence and found a reduced risk of gastric cancer associated with clozapine use48 (OR=0.35 (0.13–0.97)). The case–control study by Chen *et al* found no increase in endometrial cancer risk after exposure to clozapine74 (OR=1.14 (0.56–2.30)). The case–control study by Tiihonen *et al* found an increased risk of haematological malignancies after exposure to clozapine78 (aOR=2.94 (2.07–4.17)). Interestingly, no significant difference for non-haematological malignancies was found78 for clozapine (aOR=1.47 (1.25–1.47)); as compared with other antipsychotics: (aOR=1.30 (1.15–1.47)). Finally, the case–control study by Brainerd *et al* also found an increased prevalence of haematological malignancies after clozapine exposure in war veterans79 (OR=1.31 (1.08–1.60)).

Additionally, five database studies assessed the association between clozapine exposure and cancer prevalence. Two database studies by Szarfman *et al* and Lertxundi *et al*, assessed the association of clozapine and pituitary tumour prevalence.76 77 For clozapine, both studies showed no significant increase in pituitary tumour prevalence in subjects exposed to clozapine77 (ARR=0.9 (0.4–1.7))76; (PRR=0.98 (0.5–1.8)). Two pharmacovigilance studies by Chrétien *et al* and Dawson *et al* assessed the risk of developing haematological malignancies in subjects exposed to clozapine, due to the risk of severe haematological side effects when using clozapine.34 80 In the first study, clozapine-exposed individuals had a significantly increased prevalence of leukaemia aOR=3.54 (2.97–4.22) and malignant lymphoma, aOR=9.13, (7.75–10.77) compared with controls.34 In the second study, an excess of haematological malignancies in subjects exposed to clozapine was reported, indicating a possible increase in cases (no analysis performed).80 Finally, a database study by Uwai and Nabekura assessed the risk of non-haematological malignancies in subjects exposed to clozapine.81 The study showed a possible relationship between clozapine and multiple non-haematological malignancies including lung, gastrointestinal, oesophageal, throat malignancies and metastases to the spine81 (ROR=1.28 (1.22–1.34)).

## Discussion

The aim of this review was to assess the risk of cancer development after the use of drugs that activate the Wnt pathway in humans. 48 observational studies (online supplemental tables S2–S10) analysing the risk of cancer of six different drugs that have known Wnt activating properties were included in this systematic review. The drugs assessed in this review were VPA, lithium, cimetidine, haloperidol, olanzapine and clozapine. Most of the included studies showed no increase in cancer prevalence after being exposed to Wnt activating drugs. Most notably, there are the 18 included cohort studies, which were assessed to have low risk of bias. These studies showed no increased cancer prevalence, and in some cases even a decreased cancer prevalence. These results suggest that using medication that activates the Wnt pathway in patients does not elevate cancer prevalence.

A few included studies showed an increase in the prevalence of malignancies after usage of Wnt activating drugs. Interestingly, the included studies that showed an increase in cancer prevalence reported increased cancer prevalence for specific cancer types; there was not a systematic increase in cancer risk. The study by Zaidan *et al*, showed an increased risk of developing solid renal tumours after a median of 20 years of lithium exposure. However, as lithium is known to be nephrotoxic, and no systemic increase in cancer risk was observed, this increase in cancer prevalence could be attributed to direct toxicity, rather than the activation of the Wnt pathway.42 Chen *et al* found an increased risk of endometrial cancer after exposure to haloperidol, attributed to antipsychotic-induced hyperprolactinaemia, which is a common side effect of antipsychotics, and not to the Wnt pathway activation. Of note are both olanzapine and clozapine, which also activate the Wnt pathway, but showed no increase in endometrial cancer risk.74

One study (which had many confounders and a high risk of bias) found an increased prevalence of gastric cancer in patients who had used cimetidine for gastric ulcers compared with the general population.73 No other included studies reported an increased cancer risk after cimetidine exposure. Therefore, it is not likely that cimetidine is carcinogenic. In this context, patients with gastric ulcers are already at a higher risk of developing gastric cancer.82 A better control for this study would have been patients with gastric ulcers and no cimetidine use.

Lastly, and most notably, multiple studies found an increased prevalence of haematological malignancies in subjects that were exposed to clozapine.34 78 80 Clozapine is well-known as the first second generation (atypical) antipsychotic and gold standard drug for treatment-refractory schizophrenia, but it has many adverse effects. Agranulocytosis is a relatively common and well-known side effect of clozapine.83 Bone marrow toxicity has been described in in vitro studies.84 The pathogenesis of clozapine-induced agranulocytosis or bone marrow toxicity is still not clear; however, it is unlikely to be Wnt associated. Multiple alternative hypotheses have been described,83 all non-related to the Wnt pathway activation. In the case–control study performed by Tiihonen *et al*, they reported no differences in non-haematological cancer risk for clozapine in comparison to other antipsychotic drugs.78 Based on available data, we can conclude that subjects exposed to clozapine are at an increased risk of haematological cancers, due to direct bone marrow damage, unrelated to its Wnt pathway activating properties. The fact that the increased cancer risk in patients exposed to clozapine has only been found in haematological malignancies and not in solid tumours supports this hypothesis.

In addition to cohort and case–control studies, multiple pharmacovigilance/surveillance studies were included in this systematic review (online supplemental tables S2–S10). The pharmacovigilance/surveillance studies by Lertxundi *et al* and Szarfman *et al* showed an increased risk of developing pituitary tumours after being exposed to the antipsychotics haloperidol and olanzapine.76 77 Nonetheless, this risk was attributed to antipsychotic-induced hyperprolactinaemia, which is a common side effect of antipsychotics, and not to the Wnt pathway activation. None of the included studies showed an increased risk of non-pituitary malignancies. Therefore, we can conclude the increase in cancer risk is not caused by the Wnt activating properties of these drugs.

### Strengths and weaknesses of the review

We assessed the cancer risk of multiple drugs with laboratory proven Wnt pathway activation. Most of the included drugs activate the Wnt pathway through GSK3-Beta inhibition (table 1).85 86 Since the activation of Wnt is not their main therapeutic target, the level of Wnt activation may differ between various drugs. However, to assess all data available on the prevalence of cancer after usage of drugs that activate Wnt, we included all available mechanisms to Wnt activation. This study therefore included all papers available.

This systematic review included a complete search of all data available until 1 November 2024. Moreover, bias was minimised by using two independent authors in the screening process.

### Strengths and weaknesses of the included studies

In this review, a total of 48 studies were included, summing up extensive data on multiple drugs activating the Wnt pathway. Notably, 21 cohort studies were included, of which 18 were assessed to be subject to a low risk of bias. This leads to an extensive dataset on the cancer risk of these compounds. Opposed to the cohort studies, however, the 19 included case–control studies involved a wide variety in risk of bias and study methods. Notably, the articles regarding cimetidine, which were relatively old overall, showed a high risk of bias.

The wide variety in study designs, types of patients, cancer types and used compounds, resulting in heterogeneity in the data prevented us from conducting a meta-analysis, which results in limitations in drawing an overall conclusion regarding the cancer risk of Wnt pathway activation.

Another limitation is the drugs that were assessed in the included studies of this review. These drugs activate the Wnt pathway, but they are not specifically designed and used for their Wnt activating properties. These drugs have been in use since the 1950s, and their Wnt activating properties have been described only in the last 30 years, mainly in in vitro experiments. Novel Wnt activating drugs, like CHIR99021,87 have been produced in the past few years. However, given that these drugs have not been used clinically, their risk is not clear and has to be assessed in the future. Furthermore, included studies had considerable missing data, including data to assess dose-related cancer risk, such as duration of treatment and used dosages. In most articles, Wnt activating properties were not discussed. Finally, there were no randomised controlled trials included in this review; only observational studies were included, which are by design more at risk of bias due to the lack of randomisation.

## Conclusions

Various applications are being researched for both activating and inhibiting the Wnt pathway. Cancer risk, however, remains a big concern.29 The results from this systematic review show that, at least for the compounds included in the currently used systemic dosage, no increase in cancer prevalence was found in any of the studies included, which could be attributed to Wnt pathway activation. These findings suggest that compounds activating the Wnt pathway are, regarding cancer risk, a safe option.

Before taking this conclusion into medical practice, however, further research on higher dosages, local administration and drugs specifically designed to induce Wnt activation should determine whether the activation of the Wnt pathway is indeed a safe treatment option with regards to cancer risk.

In the regenerative therapy field, Wnt activation is a promising agent for future treatment opportunities. Based on the data in this review, we can conclude that Wnt activation by the assessed compounds leads to no increased cancer risk. Therefore, further research into Wnt activation as a treatment option should be explored.

## Data availability statement

No data are available.

## Ethics statements

### Patient consent for publication

Not applicable.

### Ethics approval

Not applicable.

## Footnotes

*   AA and NS-C are joint first authors.

*   Contributors AA: conceptualisation, data curation, formal analysis, investigation, visualisation, writing—original draft preparation. NS-C: conceptualisation, data curation, formal analysis, investigation, project administration, supervision, visualisation, writing—original draft preparation, writing—review and editing. GF: data curation, formal analysis, investigation. STB: data curation, formal analysis, investigation. RS: supervision, writing—review and editing. IS: conceptualisation, resources, project administration, supervision, writing—review and editing. LVS: conceptualisation, project administration, supervision, writing—review and editing. NS-C is the guarantor.

*   Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

*   Competing interests None declared.

*   Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

*   Provenance and peer review Not commissioned; externally peer reviewed.

*   Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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## References

1.  Nusse R, Clevers H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell 2017;169:985–99. [doi:10.1016/j.cell.2017.05.016](http://dx.doi.org/10.1016/j.cell.2017.05.016)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.cell.2017.05.016&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=28575679&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

2.  Steinhart Z, Angers S. Wnt signaling in development and tissue homeostasis. Development 2018;145:dev146589. [doi:10.1242/dev.146589](http://dx.doi.org/10.1242/dev.146589)
    
    

3.  Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov 2014;13:513–32. [doi:10.1038/nrd4233](http://dx.doi.org/10.1038/nrd4233)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1038/nrd4233&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=24981364&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

4.  Berwick DC, Harvey K. The importance of Wnt signalling for neurodegeneration in Parkinson’s disease. Biochem Soc Trans 2012;40:1123–8. [doi:10.1042/BST20120122](http://dx.doi.org/10.1042/BST20120122)
    
    [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NzoicHBiaW9zdCI7czo1OiJyZXNpZCI7czo5OiI0MC81LzExMjMiO3M6NDoiYXRvbSI7czoyNjoiL2Jtam9wZW4vMTUvNS9lMTAzMjk2LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

5.  Inestrosa NC, Montecinos-Oliva C, Fuenzalida M. Wnt signaling: role in Alzheimer disease and schizophrenia. J Neuroimmune Pharmacol 2012;7:788–807. [doi:10.1007/s11481-012-9417-5](http://dx.doi.org/10.1007/s11481-012-9417-5)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1007/s11481-012-9417-5&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=23160851&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

6.  Hu H-H, Cao G, Wu X-Q, et al. Wnt signaling pathway in aging-related tissue fibrosis and therapies. Ageing Res Rev 2020;60:S1568-1637(20)30001-5. [doi:10.1016/j.arr.2020.101063](http://dx.doi.org/10.1016/j.arr.2020.101063)
    
    

7.  Shi J, Chi S, Xue J, et al. Emerging role and therapeutic implication of Wnt signaling pathways in autoimmune diseases. J Immunol Res 2016;2016:9392132. [doi:10.1155/2016/9392132](http://dx.doi.org/10.1155/2016/9392132)
    
    

8.  Klaus A, Birchmeier W. Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008;8:387–98. [doi:10.1038/nrc2389](http://dx.doi.org/10.1038/nrc2389)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1038/nrc2389&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=18432252&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 
    
    [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000255264700018&link_type=ISI) 

9.  MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009;17:9–26. [doi:10.1016/j.devcel.2009.06.016](http://dx.doi.org/10.1016/j.devcel.2009.06.016)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.devcel.2009.06.016&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=19619488&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 
    
    [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000268373900005&link_type=ISI) 

10. Kumar KK, Burgess AW, Gulbis JM. Structure and function of LGR5: an enigmatic G-protein coupled receptor marking stem cells. Protein Sci 2014;23:551–65. [doi:10.1002/pro.2446](http://dx.doi.org/10.1002/pro.2446)
    
    

11. Zhou Y, Huang Y, Cao X, et al. WNT2 promotes cervical carcinoma metastasis and induction of epithelial-mesenchymal transition. PLoS ONE 2016;11:e0160414. [doi:10.1371/journal.pone.0160414](http://dx.doi.org/10.1371/journal.pone.0160414)
    
    

12. Lammi L, Arte S, Somer M, et al. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am J Hum Genet 2004;74:1043–50. [doi:10.1086/386293](http://dx.doi.org/10.1086/386293)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1086/386293&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=15042511&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 
    
    [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000220926100022&link_type=ISI) 

13. Gray JE, Infante JR, Brail LH, et al. A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin. Invest New Drugs 2015;33:1187–96. [doi:10.1007/s10637-015-0278-7](http://dx.doi.org/10.1007/s10637-015-0278-7)
    
    

14. Rizzieri DA, Cooley S, Odenike O, et al. An open-label phase 2 study of glycogen synthase kinase-3 inhibitor LY2090314 in patients with acute leukemia. Leuk Lymphoma 2016;57:1800–6. [doi:10.3109/10428194.2015.1122781](http://dx.doi.org/10.3109/10428194.2015.1122781)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.3109/10428194.2015.1122781&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=26735141&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

15. Leclair-Visonneau L, Rouaud T, Debilly B, et al. Randomized placebo-controlled trial of sodium valproate in progressive supranuclear palsy. Clin Neurol Neurosurg 2016;146:35–9. [doi:10.1016/j.clineuro.2016.04.021](http://dx.doi.org/10.1016/j.clineuro.2016.04.021)
    
    

16. del Ser T, Steinwachs KC, Gertz HJ, et al. Treatment of Alzheimer’s disease with the GSK-3 inhibitor tideglusib: a pilot study. J Alzheimers Dis 2013;33:205–15. [doi:10.3233/JAD-2012-120805](http://dx.doi.org/10.3233/JAD-2012-120805)
    
    

17. Georgievska B, Sandin J, Doherty J, et al. AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans. J Neurochem 2013;125:446–56. [doi:10.1111/jnc.12203](http://dx.doi.org/10.1111/jnc.12203)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1111/jnc.12203&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=23410232&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

18. Tolosa E, Litvan I, Höglinger GU, et al. A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy. Mov Disord 2014;29:470–8. [doi:10.1002/mds.25824](http://dx.doi.org/10.1002/mds.25824)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1002/mds.25824&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=24532007&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

19. Jo SJ, Shin H, Park YW, et al. Topical valproic acid increases the hair count in male patients with androgenetic alopecia: a randomized, comparative, clinical feasibility study using phototrichogram analysis. J Dermatol 2014;41:285–91. [doi:10.1111/1346-8138.12422](http://dx.doi.org/10.1111/1346-8138.12422)
    
    

20. Tosti A, Zaiac MN, Canazza A, et al. Topical application of the Wnt/β-catenin activator methyl vanillate increases hair count and hair mass index in women with androgenetic alopecia. J Cosmet Dermatol 2016;15:469–74. [doi:10.1111/jocd.12225](http://dx.doi.org/10.1111/jocd.12225)
    
    

21. Bugter JM, Fenderico N, Maurice MM. Mutations and mechanisms of WNT pathway tumour suppressors in cancer. Nat Rev Cancer 2021;21:5–21. [doi:10.1038/s41568-020-00307-z](http://dx.doi.org/10.1038/s41568-020-00307-z)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1038/s41568-020-00307-z&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=33097916&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

22. Riva G, Cilibrasi C, Bazzoni R, et al. Valproic acid inhibits proliferation and reduces invasiveness in glioma stem cells through WNT/β catenin signalling activation. Genes (Basel) 2018;9:522. [doi:10.3390/genes9110522](http://dx.doi.org/10.3390/genes9110522)
    
    

23. Taha MO, Bustanji Y, Al-Ghussein MAS, et al. Pharmacophore modeling, quantitative structure-activity relationship analysis, and in silico screening reveal potent glycogen synthase kinase-3beta inhibitory activities for cimetidine, hydroxychloroquine, and gemifloxacin. J Med Chem 2008;51:2062–77. [doi:10.1021/jm7009765](http://dx.doi.org/10.1021/jm7009765)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1021/jm7009765&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=18324764&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

24. Ochoa ELM. Lithium as a neuroprotective agent for bipolar disorder: an overview. Cell Mol Neurobiol 2022;42:85–97. [doi:10.1007/s10571-021-01129-9](http://dx.doi.org/10.1007/s10571-021-01129-9)
    
    

25. Hedgepeth CM, Conrad LJ, Zhang J, et al. Activation of the Wnt signaling pathway: a molecular mechanism for lithium action. Dev Biol 1997;185:82–91. [doi:10.1006/dbio.1997.8552](http://dx.doi.org/10.1006/dbio.1997.8552)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1006/dbio.1997.8552&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=9169052&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 
    
    [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=A1997XA02100008&link_type=ISI) 

26. Nagu P, Sharma V, Behl T, et al. Molecular insights to the Wnt signaling during alzheimer’s disorder: a potential target for therapeutic interventions. J Mol Neurosci 2022;72:679–90. [doi:10.1007/s12031-021-01940-5](http://dx.doi.org/10.1007/s12031-021-01940-5)
    
    

27. Augello G, Emma MR, Cusimano A, et al. The role of GSK-3 in cancer immunotherapy: GSK-3 inhibitors as a new frontier in cancer treatment. Cells 2020;9:1427. [doi:10.3390/cells9061427](http://dx.doi.org/10.3390/cells9061427)
    
    

28. Duda P, Akula SM, Abrams SL, et al. Targeting GSK3 and associated signaling pathways involved in cancer. Cells 2020;9:1110. [doi:10.3390/cells9051110](http://dx.doi.org/10.3390/cells9051110)
    
    

29. Huang P, Yan R, Zhang X, et al. Activating Wnt/β-catenin signaling pathway for disease therapy: Challenges and opportunities. Pharmacology & Therapeutics 2019;196:79–90. [doi:10.1016/j.pharmthera.2018.11.008](http://dx.doi.org/10.1016/j.pharmthera.2018.11.008)
    
    

30. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. PLoS Med 2021;18:e1003583. [doi:10.1371/journal.pmed.1003583](http://dx.doi.org/10.1371/journal.pmed.1003583)
    
    

31. Schardt C, Adams MB, Owens T, et al. Utilization of the PICO framework to improve searching PubMed for clinical questions. BMC Med Inform Decis Mak 2007;7:16. [doi:10.1186/1472-6947-7-16](http://dx.doi.org/10.1186/1472-6947-7-16)
    
    

32. Ouzzani M, Hammady H, Fedorowicz Z, et al. Rayyan-a web and mobile app for systematic reviews. Syst Rev 2016;5:210. [doi:10.1186/s13643-016-0384-4](http://dx.doi.org/10.1186/s13643-016-0384-4)
    
    

33. Wells GA, Shea B, O’connel D, et al. Ottawa Hospital Research Institute, Available: [http://www.ohri.ca/programs/clinical\_epidemiology/oxford.asp](http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp)
    
    

34. Chrétien B, Lelong-Boulouard V, Chantepie S, et al. Haematologic malignancies associated with clozapine v. all other antipsychotic agents: a pharmacovigilance study in VigiBase. Psychol Med 2021;51:1459–66. [doi:10.1017/S0033291720000161](http://dx.doi.org/10.1017/S0033291720000161)
    
    

35. Kaae J, Boyd HA, Hansen AV, et al. Photosensitizing medication use and risk of skin cancer. Cancer Epidemiol Biomarkers Prev 2010;19:2942–9. [doi:10.1158/1055-9965.EPI-10-0652](http://dx.doi.org/10.1158/1055-9965.EPI-10-0652)
    
    [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY2VicCI7czo1OiJyZXNpZCI7czoxMDoiMTkvMTEvMjk0MiI7czo0OiJhdG9tIjtzOjI2OiIvYm1qb3Blbi8xNS81L2UxMDMyOTYuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

36. Cohen Y, Chetrit A, Cohen Y, et al. Cancer morbidity in psychiatric patients: influence of lithium carbonate treatment. Med Oncol 1998;15:32–6. [doi:10.1007/BF02787342](http://dx.doi.org/10.1007/BF02787342)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1007/BF02787342&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=9643528&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 
    
    [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000079462400005&link_type=ISI) 

37. Pottegård A, Lash TL, Cronin-Fenton D, et al. Use of antipsychotics and risk of breast cancer: a Danish nationwide case-control study. Br J Clin Pharmacol 2018;84:2152–61. [doi:10.1111/bcp.13661](http://dx.doi.org/10.1111/bcp.13661)
    
    

38. Kristensen KB, Pedersen SA, Schmidt SAJ, et al. Use of antiepileptic drugs and risk of skin cancer: A nationwide case-control study. J Am Acad Dermatol 2020;82:326–35. [doi:10.1016/j.jaad.2019.05.055](http://dx.doi.org/10.1016/j.jaad.2019.05.055)
    
    

39. Stritzelberger J, Lang JD, Mueller TM, et al. Anti-seizure medication is not associated with an increased risk to develop cancer in epilepsy patients. J Neurol 2021;268:2185–91. [doi:10.1007/s00415-020-10379-4](http://dx.doi.org/10.1007/s00415-020-10379-4)
    
    

40. Kahan NR, Silverman B, Liphshitz I, et al. No apparent association between bipolar disorder and cancer in a large epidemiological study of outpatients in a managed care population. Int Clin Psychopharmacol 2018;33:73–8. [doi:10.1097/YIC.0000000000000197](http://dx.doi.org/10.1097/YIC.0000000000000197)
    
    

41. Tamim HM, Mahmud S, Hanley JA, et al. Antidepressants and risk of prostate cancer: a nested case-control study. Prostate Cancer Prostatic Dis 2008;11:53–60. [doi:10.1038/sj.pcan.4501003](http://dx.doi.org/10.1038/sj.pcan.4501003)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1038/sj.pcan.4501003&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=17684479&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 
    
    [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000253118200008&link_type=ISI) 

42. Zaidan M, Stucker F, Stengel B, et al. Increased risk of solid renal tumors in lithium-treated patients. Kidney Int 2014;86:184–90. [doi:10.1038/ki.2014.2](http://dx.doi.org/10.1038/ki.2014.2)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1038/ki.2014.2&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=24451323&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

43. Hallas J, Friis S, Bjerrum L, et al. Cancer risk in long-term users of valproate: a population-based case-control study. Cancer Epidemiol Biomarkers Prev 2009;18:1714–9. [doi:10.1158/1055-9965.EPI-08-0646](http://dx.doi.org/10.1158/1055-9965.EPI-08-0646)
    
    [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY2VicCI7czo1OiJyZXNpZCI7czo5OiIxOC82LzE3MTQiO3M6NDoiYXRvbSI7czoyNjoiL2Jtam9wZW4vMTUvNS9lMTAzMjk2LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

44. Velicer CM, Dublin S, White E. Cimetidine use and the risk for prostate cancer: results from the VITAL cohort study. Ann Epidemiol 2006;16:895–900. [doi:10.1016/j.annepidem.2006.03.003](http://dx.doi.org/10.1016/j.annepidem.2006.03.003)
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=16843010&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

45. Rossing MA, Scholes D, Cushing-Haugen KL, et al. Cimetidine use and risk of prostate and breast cancer, Available: [http://aacrjournals.org/cebp/article-pdf/9/3/319/3256582/ce030000319p.pdf](http://aacrjournals.org/cebp/article-pdf/9/3/319/3256582/ce030000319p.pdf)
    
    

46. Wang PS, Walker AM, Tsuang MT, et al. Dopamine antagonists and the development of breast cancer. Arch Gen Psychiatry 2002;59:1147–54. [doi:10.1001/archpsyc.59.12.1147](http://dx.doi.org/10.1001/archpsyc.59.12.1147)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1001/archpsyc.59.12.1147&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=12470131&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 
    
    [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000179710600009&link_type=ISI) 

47. Friedman GD, Habel LA, Achacoso N, et al. Haloperidol and prostate cancer prevention: more epidemiologic research needed. Perm J 2020;24:18.313. [doi:10.7812/TPP/18.313](http://dx.doi.org/10.7812/TPP/18.313)
    
    

48. Hsieh Y-H, Chan H-L, Lin C-F, et al. Antipsychotic use is inversely associated with gastric cancer risk: A nationwide population-based nested case-control study. Cancer Med 2019;8:4484–96. [doi:10.1002/cam4.2329](http://dx.doi.org/10.1002/cam4.2329)
    
    

49. Chavez A, Quesenberry CP, Darbinian J, et al. Association of valproic acid use, a potent histone deacetylase inhibitor, and melanoma risk. J Invest Dermatol 2020;140:2353–8. [doi:10.1016/j.jid.2020.04.007](http://dx.doi.org/10.1016/j.jid.2020.04.007)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.jid.2020.04.007&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=32353448&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

50. Yang B-H, Lin W-Z, Chiang Y-T, et al. Epigenetics-associated risk reduction of hematologic neoplasms in a nationwide cohort study: the chemopreventive and therapeutic efficacy of hydralazine. Front Oncol 2022;12:809014. [doi:10.3389/fonc.2022.809014](http://dx.doi.org/10.3389/fonc.2022.809014)
    
    

51. Singh G, Bell GS, Driever PH, et al. Cancer risk in people with epilepsy using valproate-sodium. Acta Neurol Scand 2012;125:234–40. [doi:10.1111/j.1600-0404.2011.01607.x](http://dx.doi.org/10.1111/j.1600-0404.2011.01607.x)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1111/j.1600-0404.2011.01607.x&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=22077648&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

52. Huang RY, Hsieh KP, Huang WW, et al. Use of lithium and cancer risk in patients with bipolar disorder: population-based cohort study. Br J Psychiatry 2016;209:393–9. [doi:10.1192/bjp.bp.116.181362](http://dx.doi.org/10.1192/bjp.bp.116.181362)
    
    [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTA6ImJqcHJjcHN5Y2giO3M6NToicmVzaWQiO3M6OToiMjA5LzUvMzkzIjtzOjQ6ImF0b20iO3M6MjY6Ii9ibWpvcGVuLzE1LzUvZTEwMzI5Ni5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

53. Lin CC, Hsieh TC, Wu LSH. Long-term use of valproic acid and the prevalence of cancers in bipolar disorder patients in a Taiwanese population: An association analysis using the National Health Insurance Research Database (NHIRD). J Affect Disord 2018;232:103–8. [doi:10.1016/j.jad.2018.02.047](http://dx.doi.org/10.1016/j.jad.2018.02.047)
    
    

54. Kang H, Gillespie TW, Goodman M, et al. Long‐term use of valproic acid in US veterans is associated with a reduced risk of smoking‐related cases of head and neck cancer. Cancer 2014;120:1394–400. [doi:10.1002/cncr.28479](http://dx.doi.org/10.1002/cncr.28479)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1002/cncr.28479&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=24664792&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

55. Salminen JK, Tammela TLJ, Auvinen A, et al. Antiepileptic drugs with histone deacetylase inhibition activity and prostate cancer risk: a population-based case-control study. Cancer Causes Control 2016;27:637–45. [doi:10.1007/s10552-016-0737-2](http://dx.doi.org/10.1007/s10552-016-0737-2)
    
    

56. George G, Garmo H, Adolfsson J, et al. Use of antiepileptic drugs and risk of prostate cancer: a nationwide case-control study in prostate cancer data base Sweden. J Oncol 2023;2023:9527920. [doi:10.1155/2023/9527920](http://dx.doi.org/10.1155/2023/9527920)
    
    

57. Li DJ, Tsai SJ, Chen TJ, et al. Exposure to psychotropic drugs and breast cancer risk in patients with bipolar disorder and major depressive disorder: a nested case-control study. Eur Arch Psychiatry Clin Neurosci 2025;275:533–43. [doi:10.1007/s00406-024-01798-9](http://dx.doi.org/10.1007/s00406-024-01798-9)
    
    

58. George A, Sturgeon SR, Hankinson SE, et al. Psychotropic medication use and postmenopausal breast cancer risk. Cancer Epidemiol Biomarkers Prev 2020;29:254–6. [doi:10.1158/1055-9965.EPI-19-0776](http://dx.doi.org/10.1158/1055-9965.EPI-19-0776)
    
    [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY2VicCI7czo1OiJyZXNpZCI7czo4OiIyOS8xLzI1NCI7czo0OiJhdG9tIjtzOjI2OiIvYm1qb3Blbi8xNS81L2UxMDMyOTYuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

59. Asgari MM, Chien AJ, Tsai AL, et al. Association between lithium use and melanoma risk and mortality: a population-based study. J Invest Dermatol 2017;137:2087–91. [doi:10.1016/j.jid.2017.06.002](http://dx.doi.org/10.1016/j.jid.2017.06.002)
    
    

60. Kessing LV, Gerds TA, Feldt‐Rasmussen B, et al. Lithium and renal and upper urinary tract tumors – results from a nationwide population‐based study. Bipolar Disord 2015;17:805–13. [doi:10.1111/bdi.12344](http://dx.doi.org/10.1111/bdi.12344)
    
    

61. Martinsson L, Westman J, Hällgren J, et al. Lithium treatment and cancer incidence in bipolar disorder. Bipolar Disord 2016;18:33–40. [doi:10.1111/bdi.12361](http://dx.doi.org/10.1111/bdi.12361)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1111/bdi.12361&link_type=DOI) 

62. Kessing LV, Knudsen MB, Rytgaard HCW, et al. Lithium versus anticonvulsants and the risk of physical disorders - Results from a comprehensive long-term nation-wide population-based study emulating a target trial. Eur Neuropsychopharmacol 2024;84:48–56. [doi:10.1016/j.euroneuro.2024.04.009](http://dx.doi.org/10.1016/j.euroneuro.2024.04.009)
    
    

63. Pottegård A, Hallas J, Jensen BL, et al. Long-term lithium use and risk of renal and upper urinary tract cancers. J Am Soc Nephrol 2016;27:249–55. [doi:10.1681/ASN.2015010061](http://dx.doi.org/10.1681/ASN.2015010061)
    
    [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiam5lcGhyb2wiO3M6NToicmVzaWQiO3M6ODoiMjcvMS8yNDkiO3M6NDoiYXRvbSI7czoyNjoiL2Jtam9wZW4vMTUvNS9lMTAzMjk2LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

64. Pottegård A, Ennis ZN, Hallas J, et al. Long-term use of lithium and risk of colorectal adenocarcinoma: a nationwide case-control study. Br J Cancer 2016;114:571–5. [doi:10.1038/bjc.2016.10](http://dx.doi.org/10.1038/bjc.2016.10)
    
    

65. Møller H, Lindvig K, Klefter R, et al. Cancer occurrence in a cohort of patients treated with cimetidine. Gut 1989;30:1558–62. [doi:10.1136/gut.30.11.1558](http://dx.doi.org/10.1136/gut.30.11.1558)
    
    [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiZ3V0am5sIjtzOjU6InJlc2lkIjtzOjEwOiIzMC8xMS8xNTU4IjtzOjQ6ImF0b20iO3M6MjY6Ii9ibWpvcGVuLzE1LzUvZTEwMzI5Ni5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

66. Rossing MA, Scholes D, Cushing-Haugen KL, et al. Cimetidine use and risk of prostate and breast cancer, 2000. Available: [http://aacrjournals.org/cebp/article-pdf/9/3/319/3256582/ce030000319p.pdf](http://aacrjournals.org/cebp/article-pdf/9/3/319/3256582/ce030000319p.pdf)
    
    

67. Coogan PF, Zhang Y, Palmer JR, et al. Cimetidine and other histamine2-receptor antagonist use in relation to risk of breast cancer. Cancer Epidemiol Biomarkers Prev 2005;14:1012–5. [doi:10.1158/1055-9965.EPI-04-0547](http://dx.doi.org/10.1158/1055-9965.EPI-04-0547)
    
    [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY2VicCI7czo1OiJyZXNpZCI7czo5OiIxNC80LzEwMTIiO3M6NDoiYXRvbSI7czoyNjoiL2Jtam9wZW4vMTUvNS9lMTAzMjk2LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

68. Holly EA, Lele C. Non-Hodgkin’s lymphoma in HIV-positive and HIV-negative homosexual men in the San Francisco Bay Area: allergies, prior medication use, and sexual practices. J Acquir Immune Defic Syndr Hum Retrovirol 1997;15:211–22. [doi:10.1097/00042560-199707010-00005](http://dx.doi.org/10.1097/00042560-199707010-00005)
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=9257656&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 
    
    [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=A1997XP28100005&link_type=ISI) 

69. Schumacher MC, Jick SS, Jick H, et al. Cimetidine use and gastric cancer. Epidemiology (Sunnyvale) 1990;1:251. [doi:10.1097/00001648-199005000-00012](http://dx.doi.org/10.1097/00001648-199005000-00012)
    
    

70. Møller H, Nissen A, Mosbech J. Use of cimetidine and other peptic ulcer drugs in Denmark 1977-1990 with analysis of the risk of gastric cancer among cimetidine users. Gut 1992;33:1166–9. [doi:10.1136/gut.33.9.1166](http://dx.doi.org/10.1136/gut.33.9.1166)
    
    [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiZ3V0am5sIjtzOjU6InJlc2lkIjtzOjk6IjMzLzkvMTE2NiI7czo0OiJhdG9tIjtzOjI2OiIvYm1qb3Blbi8xNS81L2UxMDMyOTYuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

71. Mathes RW, Malone KE, Daling JR, et al. Relationship between Histamine2-receptor antagonist medications and risk of invasive breast cancer. Cancer Epidemiol Biomarkers Prev 2008;17:67–72. [doi:10.1158/1055-9965.EPI-07-0765](http://dx.doi.org/10.1158/1055-9965.EPI-07-0765)
    
    [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiY2VicCI7czo1OiJyZXNpZCI7czo3OiIxNy8xLzY3IjtzOjQ6ImF0b20iO3M6MjY6Ii9ibWpvcGVuLzE1LzUvZTEwMzI5Ni5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

72. Colin-Jones DG, Langman MJ, Lawson DH, et al. Post-cimetidine surveillance for up to ten years: incidence of carcinoma of the stomach and oesophagus. Q J Med 1991;78:13–9. [doi:10.1093/oxfordjournals.qjmed.a068520](http://dx.doi.org/10.1093/oxfordjournals.qjmed.a068520)
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=1670060&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

73. Colin-Jones DG, Langman MJ, Lawson DH, et al. Postmarketing surveillance of the safety of cimetidine: 12 month mortality report. BMJ 1983;286:1713–6. [doi:10.1136/bmj.286.6379.1713](http://dx.doi.org/10.1136/bmj.286.6379.1713)
    
    [Abstract/FREE Full Text](http://bmjopen.bmj.com/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiYm1qIjtzOjU6InJlc2lkIjtzOjEzOiIyODYvNjM3OS8xNzEzIjtzOjQ6ImF0b20iO3M6MjY6Ii9ibWpvcGVuLzE1LzUvZTEwMzI5Ni5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

74. Chen W-L, Nithiyanantham S, Mao Y-C, et al. Haloperidol and other antipsychotics exposure before endometrial cancer diagnosis: a population-based case-control study. Clin Psychopharmacol Neurosci 2022;20:526–35. [doi:10.9758/cpn.2022.20.3.526](http://dx.doi.org/10.9758/cpn.2022.20.3.526)
    
    

75. Maeshima T, Iijima R, Watanabe M, et al. Effect of antipsychotics on breast tumors by analysis of the Japanese Adverse Drug Event Report database and cell-based experiments. J Pharm Health Care Sci 2021;7:13. [doi:10.1186/s40780-021-00199-7](http://dx.doi.org/10.1186/s40780-021-00199-7)
    
    

76. Lertxundi U, Erezuma I, Hernandez R, et al. Antipsychotics and pituitary tumors: an analysis of the European pharmacovigilance database (EudraVigilance). Int Clin Psychopharmacol 2019;34:89–92. [doi:10.1097/YIC.0000000000000247](http://dx.doi.org/10.1097/YIC.0000000000000247)
    
    

77. Szarfman A, Tonning JM, Levine JG, et al. Atypical antipsychotics and pituitary tumors: a pharmacovigilance study. Pharmacotherapy 2006;26:748–58. [doi:10.1592/phco.26.6.748](http://dx.doi.org/10.1592/phco.26.6.748)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1592/phco.26.6.748&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=16716128&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 
    
    [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000238011100002&link_type=ISI) 

78. Tiihonen J, Tanskanen A, Bell JS, et al. Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland. Lancet Psychiatry 2022;9:353–62. [doi:10.1016/S2215-0366(22)00044-X](http://dx.doi.org/10.1016/S2215-0366(22)00044-X)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/s2215-0366(22)00044-x&link_type=DOI) 

79. Brainerd DR, Alexander B, Tague MJ, et al. Association between clozapine exposure and risk of hematologic malignancies in veterans with schizophrenia. J Clin Psychiatry 2024;85:23m15149. [doi:10.4088/JCP.23m15149](http://dx.doi.org/10.4088/JCP.23m15149)
    
    

80. Dawson JL, Sluggett JK, Procter NG, et al. Hematological and other cancers in people using clozapine: analysis of australian spontaneous reports between 1995 and 2020. J Clin Psychopharmacol 2023;43:333–8. [doi:10.1097/JCP.0000000000001699](http://dx.doi.org/10.1097/JCP.0000000000001699)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1097/jcp.0000000000001699&link_type=DOI) 

81. Uwai Y, Nabekura T. Relationship between clozapine and non-hematological malignant tumors: a pharmacovigilance analysis using the FDA adverse event reporting system database. Drugs Real World Outcomes 2024;11:185–93. [doi:10.1007/s40801-024-00417-2](http://dx.doi.org/10.1007/s40801-024-00417-2)
    
    

82. Søgaard KK, Farkas DK, Pedersen L, et al. Long-term risk of gastrointestinal cancers in persons with gastric or duodenal ulcers. Cancer Med 2016;5:1341–51. [doi:10.1002/cam4.680](http://dx.doi.org/10.1002/cam4.680)
    
    

83. Legge SE, Walters JT. Genetics of clozapine-associated neutropenia: recent advances, challenges and future perspective. Pharmacogenomics 2019;20:279–90. [doi:10.2217/pgs-2018-0188](http://dx.doi.org/10.2217/pgs-2018-0188)
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=30767710&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

84. Pereira A, Dean B. Clozapine bioactivation induces dose-dependent, drug-specific toxicity of human bone marrow stromal cells: a potential in vitro system for the study of agranulocytosis. Biochem Pharmacol 2006;72:783–93. [doi:10.1016/j.bcp.2006.06.006](http://dx.doi.org/10.1016/j.bcp.2006.06.006)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1016/j.bcp.2006.06.006&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=16844094&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 

85. Furuta T, Sabit H, Dong Y, et al. Biological basis and clinical study of glycogen synthase kinase- 3β-targeted therapy by drug repositioning for glioblastoma. Oncotarget 2017;8:22811–24. [doi:10.18632/oncotarget.15206](http://dx.doi.org/10.18632/oncotarget.15206)
    
    

86. Sutton LP, Honardoust D, Mouyal J, et al. Activation of the canonical Wnt pathway by the antipsychotics haloperidol and clozapine involves dishevelled-3. J Neurochem 2007;102:153–69. [doi:10.1111/j.1471-4159.2007.04527.x](http://dx.doi.org/10.1111/j.1471-4159.2007.04527.x)
    
    [CrossRef](http://bmjopen.bmj.com/lookup/external-ref?access_num=10.1111/j.1471-4159.2007.04527.x&link_type=DOI) 
    
    [PubMed](http://bmjopen.bmj.com/lookup/external-ref?access_num=17472703&link_type=MED&atom=%2Fbmjopen%2F15%2F5%2Fe103296.atom) 
    
    [Web of Science](http://bmjopen.bmj.com/lookup/external-ref?access_num=000247205700014&link_type=ISI) 

87. Yoshida Y, Soma T, Matsuzaki T, et al. Wnt activator CHIR99021-stimulated human dermal papilla spheroids contribute to hair follicle formation and production of reconstituted follicle-enriched human skin. Biochem Biophys Res Commun 2019;516:599–605. [doi:10.1016/j.bbrc.2019.06.038](http://dx.doi.org/10.1016/j.bbrc.2019.06.038)