2023 Impact Factor
2023 Impact Factor
Cancer remains the leading cause of death worldwide, accounting for almost 10 million deaths each year (Sung et al., 2021). Mutations in specific genes may initiate cancer and it is characterized by features such as uncontrolled growth and constant cell proliferation. Initial anticancer therapy can be followed by recurrence, and invasive metastasis can be both painful and fatal (Bertram, 2000). Studies have been conducted to better understand the complex mechanisms and to find remedies or preventions (Golemis et al., 2018). Despite ongoing efforts to find a cure, we have not yet achieved a complete cure (Malik et al., 2021).
Breast cancer is common, and in the United States alone, nearly 30 thousand people are diagnosed every year (Siegel et al., 2022). Treatment of breast cancer includes surgery, radiation therapy, and chemotherapy. Depending on the presence of hormone receptors for either estrogen and progesterone, hormone therapy can be effective. Additionally, more recent targeted therapies, such as those targeting HER2, are available options (Jacobs et al., 2022). Some of the cancer patients suffer from the lack of hormone receptors and HER2, as neither hormone antagonists nor antibodies against HER2 would work in these cases (Cleator et al., 2007). The lack of these three receptors in breast cancer is referred triple-negative breast cancer (TNBC), which is more invasive and metastatic with a poorer prognosis compared to other types of breast cancer (Yin et al., 2020). Some subtypes of TNBC may respond to epidermal growth factor receptor antagonists (Livasy et al., 2006), and several therapeutics targeting TNBC are currently under development. Among these approaches, PARP inhibition (Dent et al., 2013) and immunotherapy (Kwapisz, 2021) appear promising, and more development in TNBC treatment would improve the therapeutic outcomes in TNBC patients.
JAK2/STAT3 signaling pathway regulates diverse biological processes such as development, stem cell maintenance, inflammation, and cell survival and death (Marotta et al., 2011). Modulation of JAK2/STAT3 signaling pathaway in TNBC cells may lead to cancer cell death (Shakya et al., 2022). Several studies examined the effect of alteration of JAK2/STAT3 signaling axis on the TNBC cells: a phase II study of ruxolitinib showed an anticancer effect of a JAK1/2 inhibitor in TNBC patients (Stover et al., 2018). In addition, salidroside inhibited the invasion of TNBC cells by inhibiting STAT3 signaling (Kang et al., 2018). The activation of the JAK2/STAT3 signaling pathway is associated with cancer cell growth, making it a plausible target for treating TNBC (Wang and Sun, 2014).
Dopamine is a well-known neurotransmitter involved with several brain functions including rewards and motivation. Interestingly, a study has shown that schizophrenic patients treated with dopamine receptor antagonists have lower incidents of cancers (Dalton et al., 2005). Moreover, the patients with Parkinson’s disease have decreased incidence of most cancers (Driver et al., 2007). These studies suggest that dopamine receptors are distributed in peripheral tissues, and antagonizing dopamine receptors may result in a decreased incidence of cancer. In vitro screening with psychotropic drugs identified the anticancer activity of phenothiazines as early as 1978 (Driscoll et al., 1978). The upregulation of dopamine receptor D2 (DRD2), a type of dopamine receptor, is often found in many cancers and DRD2 is related to cancer stemness (Weissenrieder et al., 2019). DRD2 has been identified as either a biomarker of cancer prognosis or a possible target in gastric cancer (Mu et al., 2017), endometrial cancer (Pierce et al., 2021), breast cancer (Gholipour et al., 2018) and so on. Domperidone is a DRD2 antagonist that has been used to treat nausea and vomiting since 1978 (Barone, 1999). In this report, we studied whether domperidone could induce apoptosis in TNBC BT-549 and CAL-51 cells.
Domperidone, N-acetyl cysteine (NAC), and Mito-TEMPO were obtained from Sigma Aldrich (St. Louis, MO, USA). Primary antibodies against the cleaved forms of caspases-3, -7, -8, and -9, cleaved PARP, Bax, Bak, superoxide dismutase (SOD) 1, cyclin D1, CDK2, CDK4, STAT1, STAT3, p-STAT1, p-STAT3 (Ser727), p-STAT3 (Tyr705), HSP90, JAK2, p-JAK2, ERK, p-ERK, JNK, p-JNK, p38, and p-p38, were purchased from Cell Signaling Technology (Denver, CO, USA). Antibodies against Bcl-2, Bcl-xL, SOD2, cyclins (A, D2, D3, and E), p16, p21, p27, p53, p-JAK1 were obtained from Santa Cruz Biotechnology (Dallas, TX, USA). In addition, anti-survivin antibody was purchased from Novus Biologicals (Centennial, CO, USA), and anti-β-actin antibody was from Sigma Aldrich (Burlington, MA, USA). Anti-catalase and anti-cyclin B antibodies were obtained from Abcam (Cambridge, UK), and anti-JAK1 antibody was from Millipore (Burlington, MA, USA). Anti-CDK1 antibody and all secondary antibodies conjugated with the horse-radish peroxidase (HRP) were purchased from Thermo Fisher (Waltham, MA, USA).
The human breast cancer cell lines BT-549 and CAL-51 were from American Type Culture Collection (Manassas, VA, USA), and cultured in DMEM medium (Hyclone, Logan, UT, USA) supplemented with 10% fetal bovine serum (Hyclone) and 1% penicillin/streptomycin (Hyclone). The cells were incubated at 37°C in a 5% CO2 humidified incubator. Unless stated otherwise, the effects of domperidone on TNBC cells were determined with varying concentration of domperidone (0, 10, 20, and 50 µM) after incubating for 24 h. Dimethyl sulfoxide (Sigma Aldrich) was used as the vehicle.
QuantiMaxTM WST assay reagent (BioMax, Seoul, Korea) was used to assess cell viability following the manufacturer’s manual. First, BT-549 and CAL051 cells were seeded in quadruplicate into a 48 well plate (1×104 cells/ well) and grown for 24 h at 37°C in a 5% CO2 incubator. The cells were then treated with domperidone at 0, 5, 10, 20, 50, 75, and 100 µM. After 24 or 48 h treatment with domperidone, the cells were incubated with QuantiMaxTM WST reagent, and the absorbance was measured at 450 nm with a microplate reader (BMG Labtech, Ortenberg, Germany).
To detect the apoptosis of BT-549 and CAL-51 cells, Annexin V-fluorescein isothiocyanate apoptosis detection kit (BD Biosciences, San Diego, CA, USA) was used. Briefly, harvested cells were washed twice with phosphate-buffered saline (PBS) containing 0.1% bovine serum albumin (BSA), and resuspended in 1× binding buffer containing Annexin V and propidium iodide (PI; Life Technologies, Carlsbad, CA, USA). Fluorescence intensity was measured by flow cytometry using a FACSCaliburTM flow cytometer (BD Biosciences).
For cell cycle analysis, the cells treated with domperidone were washed with PBS containing 0.1% BSA and fixed in ice-cold ethanol (100%) overnight. The fixed cells were washed again with PBS with 0.1% BSA and stained with PI solution (50 µg/mL) containing RNase A 100 μg/mL (Biosesang, Daejeon, Korea) by incubating for 30 min at room temperature. The DNA content was assessed by flow cytometry.
To quantify mitochondrial superoxide, the cells were treated with domperidone and stained with specific dyes. The content of mitochondrial superoxide was measured by flow cytometry after staining the cells with MitoSOXTM Red (5 µM; Thermo Fisher) after 30 min. incubation. The mitochondrial membrane potential (MMP) was measured after staining the cells with 3,3’-dihexyloxacarbocyanine iodide (DiOC6) (Life Technologies).
The cells treated with domperidone were harvested, washed with PBS, and lysed with RIPA buffer (1 mM NaF, 1 mM sodium orthovanadate, 0.1 mM phenylmethylsulfonyl fluoride, and a protease inhibitor cocktail). The protein yield was measured using Pierce Coomassie (Bradford) protein Assay Kit (Thermo Fisher) according to the manufacturer’s instructions. Protein samples were resolved by sodium dodecyl sulfate polyacrylamide gel electrophoresis (10% or 15% polyacrylamide). The resolved proteins were transferred to a polyvinylidene difluoride membrane (EMD Millipore Corporation, Billerica, MA, USA). The membrane was blocked with in Tris-buffered saline–Tween® 20 detergent (TBST) containing 5% skim milk for 1 h at room temperature, then incubated with primary antibodies [1;1,000 dilution in 2% skim milk in TBST] overnight at 4°C. The membrane incubated with the primary antibodies was washed with TBST and incubated with the corresponding secondary antibodies [1:5,000 dilution] for 2 h at room temperature. The proteins on the membrane were visualized by chemiluminescence using Amersham enhanced chemiluminescence reagent (GE Lifesciences, Piscataway, NJ, USA).
Data are presented as the mean ± standard deviation (SD). Single comparisons were performed using the Student’s t-test. Data analysis was performed using SigmaStat 3.5 (Systat Software, Inc., San Jose, CA, USA). A probability (p) value less than 0.05 was considered statistically significant.
To investigate the effect of domperidone on the viability of TNBC BT-549 and CAL-51 cells, we performed WST assay. Domperidone significantly reduced cell viability in a dose- and time-dependent manner (Fig. 1A). The IC50 values of the inhibition of cell growth were 55.1 µM at 24 h and 56.5 µM at 48 h for BT-549 cells, and 53.2 µM at 24 h and 43.7 µM at 48 h for CAL-51 cells. The flow cytometry analysis after staining with annexin V/PI revealed that the percentage of apoptotic cells increased from 14.6% to 18.4%, 16.3%, and 23.1% as the concentration of domperidone increased from 0 to 10, 20, and 50 µM, respectively, for BT-549 cells. Similarly, the ratio of cells undergoing apoptosis increased from 7.8 to 8.9, 12.2, and 54.6% as the concentration of domperidone increases (Fig. 1B). Furthermore, we observed the cleavage of caspases (caspases-3, -7, -8, and 9) and PARP protein by immunoblot analysis (Fig. 1C). These results suggest that domperidone indeced cell death and activated the caspase cascade in both TNBC cells.
Figure 1. Antiproliferative effect of domperidone in TNBC cells. (A) TNBC BT-549 and CAL-51 cells were treated with domperidone (0, 5, 10, 20, 50, and 100 µM) for 24 (black) and 48 h (gray) and cell viability was determined by WST cell viability assay. The data are shown as the mean ± SD (n=4). **p<0.01 compared to the control group (0 µM domperidone). (B) BT-549 and CAL-51 cells treated with varying concentrations of domperidone (0, 10, 20, and 50 µM) for 24 h were analyzed by flow cytometry with annexin V/PI staining. (C) The level of cleaved forms of caspase-3, -7, -8, and -9, and PARP were monitored by immunoblot. β-Actin was used as the loading control.
To demonstrate if the domperidone-induced apoptosis is involves the mitochondrial pathway, we monitored the protein levels of Bcl-2 family members using immunoblot (Fig. 2A). The incubation of TNBC cells with domperidone did not alter the levels of Bax and Bak, the pro-apoptotic Bcl-2 proteins. However, we observed a decrease in the levels of Bcl-2 and Bcl-xL proteins. This suggests that the balance of Bcl-2 family proteins in mitochondria was disrupted by domperidone treatment. In addition, we observed a 52.62% reduction in mitochondrial membrane potential after treatment with 50 µM of domperidone in BT-549 cells (Fig. 2B). These results indicate that domperidone activates the mitochondrial apoptotic pathway.
Figure 2. Disturbance of bcl-2 family proteins by domperidone. (A) TNBC BT-549 and CAL-51 cells were treated with domperidone (0, 10, 20, and 50 µM) for 24 h and the levels of Bcl-2 family proteins Bcl-2, Bcl-xL, Bax, and Bak were monitored by immunoblot. β-Actin was used as the loading control. (B) The mitochondrial membrane potential was measured by flow cytometry with DiOC6 staining. The bar graphs represent the mean ± SD (n=3). *p<0.05 compared to the control group.
Reactive oxygen species (ROS) are known to be involved in various mechanisms that induce apoptosis (Richa et al., 2020). To determine whether domperidone treatment regulates the generation of mitochondrial superoxide, we measured mitochondrial superoxide levels using flow cytometry after staining with MitoSOX Red. The mitochondrial superoxide levels increased by 3.11-fold in BT-549 cells and 6.23-fold in CAL-51 cells after domperidone treatment (Fig. 3A). Next, we examined whether the cell death by domperidone could be prevented by a superoxide scavenger. Pre-treating TNBC cells with Mito-TEMPO, an antioxidant targeted to mitochondria, at a concentration of 100 nM, resulted in a 19.7% decrease in domperidone-induced cell death in BT-549 cells and a 22.1% decrease in CAL-51 cells (Fig. 3B). The levels of catalase, SOD1 and SOD2, which are involved in the regulation of ROS generation, remained relatively stable in the presence of domperidone (data not shown). These results suggest the involvement of mitochondrial superoxide in domperidone-induced apoptosis.
Figure 3. Induction of mitochondrial ROS by domperidone. (A) TNBC BT-549 and CAL-51 cells were treated with domperidone (0, 10, 20, and 50 µM) for 24 h and the levels of mitochondrial superoxide were analyzed by flow cytometry with MitoSOXTM Red staining. The bar graphs represent the mean ± SD (n=3). *p<0.05 and **p<0.01 compared to the control group. (B) TNBC cells were pretreated with 100 nM of Mito-TEMPO for 3 h before domperidone treatment (100 µM for 24 h). The cell viability was measured by WST assay. **p<0.01 compared to the domperidone treated group.
To determine whether domperidone-induced cell death was associated with cell cycle arrest, we analyzed the cell cycle phase populations of TNBC cells using flow cytometry. In BT-549 cells, the proportion of cells in the subG1 phase expanded from 2.1% to 3.8% after treatment of 50 µM of domperidone. Moreover, the percentage of cells in the polyploidy phase increased from 12.9% to 26.9%, and this increase in polyploidy cells was just observed in BT-549 cells. In CAL-51 cells, the ratio of cells in the subG1 phase increased from 2.3% to 12.6% after domperidone treatment. Furthermore, the proportion of BT-549 cells in the G2/M phase increased from 20.1% to 29.4% upon treatment with domperidone (Fig. 4A). The levels of CDKs and cyclin A, B, and D, as assessed by immunoblot analysis, decreased with domperidone treatment, while the level of cyclin E remained constant (Fig. 4B). In addition, the levels of CDK inhibitors, p16, p21, and p27 did not increase after domperidone treatment (Fig. 4C).
Figure 4. Interference of cell cycle progression by domperidone. TNBC BT-549 and CAL-51 cells were treated with domperidone (0, 10, 20, and 50 µM) for 24 h. (A) Cell cycle analysis by flow cytometry with PI staining. (B) The immunoblot analysis of cell cycle related proteins cyclins A, B, D1, D2, D3, and E, and CDK1, 2, and 4. β-Actin was used as the loading control. (C) The immunoblot analysis of CDK inhibitors p16, p21, and p27, and p53.
We then examined the effects of domperidone on JAK2 and STAT3 proteins by immunoblot analysis, as the fate of many cancer cells is controlled by JAK2/STAT3 signaling pathway. We observed that the level of JAK1, JAK2, STAT1, and STAT3 proteins remained relatively unchanged after domperidone treatment in both BT-549 and CAL-51 cells. However, the phosphorylation of JAK1 and JAK2 dramatically decreased following treatment with domperidone. In addition, the levels of phosphorylated STAT1 (p-STAT1), p-STAT3 (Ser727), and pSTAT3 (Tyr705) was decreased in a dose dependent manner by domperidone treatment (Fig. 5A). Next, we monitored the levels of protein kinases involved in the cell survival signaling, such as ERK, JNK, and p38, and found that their protein levels remained unchanged. For the rest of protein kinases analyzed, ERK, JNK, and p38, neither protein level nor phosphorylation status changed (Fig. 5B).
Figure 5. Regulation of JAK2/STAT3 signaling by domperidone. TNBC BT-549 and CAL-51 cells were treated with domperidone (0, 10, 20, and 50 µM) for 24 h. (A) The immunoblot analysis of proteins involved in Jak/STAT signaling pathways. (B) The immunoblot analysis of proteins involved with MAP kinase signaling pathway. β-Actin was used as the loading control.
We investigated the effects of domperidone on the expression of dopamine receptor D series using immunoblot analysis. After treating BT-549 and CAL-51 cells with domperidone for 24 h, we observed a noticeable decrease in the protein levels of dopamine D2-like receptors (DRD2, DRD3, and DRD4), while the levels of dopamine D1-like receptors (DRD1 and DRD5) remained relatively stable (Fig. 6A).
Figure 6. Downregulation of the dopamine D2-like receptor by domperidone. (A) TNBC BT-549 and CAL-51 cells were treated with domperidone (0, 10, 20, and 50 µM) for 24 h. The immunoblot analysis of dopamine receptors DRD1 through DRD5. β-Actin was used as the loading control. (B) The fold of induction in the mRNA level analyzed by reverse transcription polymerase chain reaction. Black bars: control (0 µM domperidone). Grey bars: domperidone treatment (50 µM) for 24 h. **p<0.01 compared to the non-treated control. ND, not detected.
To determine whether the changes in protein levels of dopamine receptors were regulated at the mRNA level, we analyzed the expression of mRNAs for dopamine receptors, DRD1 through DRD5 using reverse transcription-polymerase chain reaction (RT-PCR). In BT-549 cells, domperidone induced significant downregulation of mRNA levels of DRD1, DRD2, and DRD5 at 50 µM. However, in CAL-51 cells, we observed an increase in the levels of mRNAs encoding DRD1, DRD2, and DRD5 following domperidone treatment. Notably, the mRNA for DRD3 and DRD4 was not detected in three independent RT-PCR analyses (Fig. 6B). These results indicate that domperidone inhibited the protein expression of D2-like dopamine receptors, however this was not related to the regulation of mRNA levels for D series dopamine receptors.
Domperidone, derived from benzimidazole, is a potent antagonist of DRD2 (Barone, 1999). It has been widely used to relieve vomiting and nausea (Fragen and Caldwell, 1978), and the antiemetic effect is particularly useful in patients undergoing antineoplastic chemotherapy (Bakowski, 1984). Unlike other antiemetics like hydroxyzine, domperidone exerts its effects peripherally as it does not readily cross the blood-brain barrier (Barone, 1999). To date, there is no study reporting the cytotoxic effect of domperidone on cancer cells. This is the first report on the anticancer activity of domperidone in human TNBC BT-549 and CAL-51 cells.
The cell viability assay demonstrated that the proliferation of TNBC cells was inhibited by domperidone in dose- and time-dependent manner (Fig. 1A, 1B). The proliferation of cancer cells could be blocked either by initiating the apoptotic pathway, or inactivating the survival pathway (Wong, 2011), and the induction of apoptosis could be a promising strategy for antineoplastic therapy (Kang et al., 2023). Therefore, we investigated whether domperidone induced apoptosis in TNBC BT-549 and CAL-51 cells, given that we observed its cytotoxic effects on these cells. The annexin V/PI apoptosis assay revealed that domperidone increased the percentage of apoptotic cells (Fig. 1B). During the progress of apoptosis, the activation of caspase cascade is a pivotal event (Budihardjo et al., 1999). As we pursued understanding the molecular mechanisms of domperidone-induced apoptosis, we observed the activation of caspases-3, 7, 8, and 9, as well as the cleavage of PARP (Fig. 1C). In addition, we noted a correlation between the activation of caspases and the decrease in MMP (Fig. 2B), and a shift in the balance of Bcl-2 family proteins (Fig. 2A).
With activation of the caspase cascade, we observed an increase in mitochondrial superoxide in TNBC cells treated with domperidone. When we analyzed mitochondrial superoxide using flow cytometry with MitoSOXTM Red staining, we found an increase in mitochondrial superoxide in TNBC cells treated with domperidone (Fig. 3A). Furthermore, we found that Mito-TEMPO at a low concentration (100 nM) was prevented the apoptosis induced by domperidone (Fig. 3B), indicating the involvement of mitochondrial superoxide in regulating domperidone-induced apoptosis. Notably, the levels of proteins known as ROS detoxifying enzymes, including catalase, SOD1, and SOD2, were not altered by domperidone treatment (data not shown) suggesting the involvement of other factors in the regulation of mitochondrial superoxide in TNBC cells treated with domperidone.
The regulation on cell cycle plays a significant role in the progression of apoptosis (Vermeulen et al., 2003). Therefore, we analyzed the cell cycle distribution in the TNBC cells BT-549 and CAL-51. The cell population in subG1 phase increased in both TNBC cells treated with domperidone (Fig. 4A), indicating that domperidone induced apoptosis in TNBC cells. In addition, we observed the ratio of cells in polyploidy and G2/M phase increased after domperidone treatment in BT-549 cells. Polyploidy is a common phenomenon which occurs in human cancers (Was et al., 2022). The increase in polyploidy cells in these cancers occurs due to endoreplication or cell fusion, and polyploidy formation might be triggered in response to various genotoxic stresses including chemotherapeutics, radiation, hypoxia, and oxidative stress (Wolf et al., 1996; Lopez-Sanchez et al., 2014; Mirzayans et al., 2017). However, these changes were not observed in CAL-51 cells, suggesting that the effect of domperidone on the cell cycle may vary among different cell lines. In immunoblot analysis, we observed a decrease in the levels of cyclins (A, B, and D) except for cyclin E and CDKs in TNBC cells treated with domperidone. Interestingly, the level of cyclin E increased slightly in BT-549 cells (Fig. 4B). However, it is doubtful whether this slight increase in cyclin E contributed to the downregulation of cell cycle progression in these cells, considering the overall decrease in the levels of cyclins and CDKs. On the other hand, the accumulation of cyclin E might be related to the polyploidy that appeared in BT-549 cells (Nakayama et al., 2000). Contrary to cyclins and CDKs, the level of CDK inhibitors, p16, p21, and p27, remained relatively unchanged after treatment with domperidone (Fig. 4C). These results, taken together, suggest that domperidone induced the apoptosis in the TNBC cells by downregulating overall cell cycle regulators rather than targeting specific targets.
The survival of cancer cells is regulated by various signaling pathways such as PI3K/Akt and JAK2/STAT3 pathways (Rascio et al., 2021; Mengie Ayele et al., 2022). Improper control of the JAK2/STAT3 signaling pathway can lead to the proliferation of cancer cells (Lee et al., 2019). STAT3 is a well-known transcription factor that modulates diverse biological processes including cell growth, differentiation, and apoptosis (Li et al., 2023). JAK phosphorylates STAT3, leading to the dimerization of STAT3. The dimerized STAT3 promotes the expression of several oncogenes. In this study, we examined whether domperidone interfered with the JAK2/STAT3 signaling pathway in the TNBC cells. We found that the protein levels of JAK and STAT3 was not altered by domperidone treatment. However, the phosphorylation of these proteins was decreased by domperidone treatment in a dose dependent manner (Fig. 5A). These results suggest that domperidone downregulated JAK2/STAT3 signaling pathway by interfering with the phosphorylation. Then, we analyzed the levels of protein kinases related to cell survival signaling including ERK, JNK, and p38. We did not observe the significant changes these kinases in protein expression and phosphorylation (Fig. 5B). Therefore, it appears that the increase in mitochondrial superoxide induced by domperidone in TNBC cells is not regulated by JNK or p38, which are known to play important roles in reactive oxygen species-mediated signaling.
To uncover the mechanisms underlying the apoptosis induced by domperidone, we examined the protein levels of dopamine receptor D series using immunoblot. Surprisingly, a 24 h incubation in the presence of domperidone resulted in the downregulation of dopamine receptors D2, D3 and D4, whereas the levels of DRD1 and DRD5 remained (Fig. 6A). Our findings appear to contradict the previous study with a zebrafish model, where DRD2 was upregulated by domperidone (Shontz et al., 2018), implying potential species- and tissue-specific differences. Indeed, the downregulation of G protein-coupled receptor by antagonists is not easily comprehended. Exposure to the antagonist of G protein-coupled receptor for a long period of time may induce the increase in the expression of G protein-coupled receptors as a compensation. In this study, the duration of exposure was relatively short, and our results do not align with previous studies. Nevertheless, the correlation between the induction of apoptosis and the downregulation of DRD2 can be easily understood considering the protective role of DRD2 in conditions such as myocardial ischemia (Li et al., 2014), and Parkinson’s disease model (Wu et al., 2018). In earlier studies, thioridazine, a DRD2 antagonist was shown to induce the cell death of cervical cancer SiHa cells (Mao et al., 2015). Thioridazine reportedly inhibits STAT3 to inhibit the self-renewal of breast cancer cells in a DRD2-dependent manner (Tegowski et al., 2018).
In conclusion, we demonstrated that domperidone downregulated the expression of cyclins and CDKs, activated the mitochondrial apoptotic pathway, increased the generation of mitochondrial superoxide, inhibited STAT3 signaling. These findings raise an intriguing possibility: targeting DRD2 with domperidone could potentially be an effective strategy for treating TNBC cells, and calls for further investigation.
This research was supported by Basic Science Research program through the National Research Foundation Korea Funded by the Ministry of Education, Science and Technology (NRF-2018R1D1A1A02050495 and NRF-2021R1A2C1014399).
The authors claim no conflicts of interest.
Funding Information
National Research Foundation of Korea Ministry of Education, Science and Technology |
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