Edited by: Teresita Padilla-Benavides, Wesleyan University, United States
Reviewed by: Marco Cordani, IMDEA Nanociencia, Spain; Isaac Cervantes Sandoval, Georgetown University, United States
This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Gastrointestinal cancers (GICs) are the most common human tumors worldwide. Treatments have limited effects, and increasing global cancer burden makes it necessary to investigate alternative strategies such as drug repurposing. Interestingly, it has been found that psychiatric drugs (PDs) are promising as a new generation of cancer chemotherapies due to their anti-neoplastic properties. This review compiles the state of the art about how PDs have been redirected for cancer therapeutics in GICs. PDs, especially anti-psychotics, anti-depressants and anti-epileptic drugs, have shown effects on cell viability, cell growth, inhibition of proliferation (cell cycle arrest), apoptosis promotion by caspases activation or cytochrome C release, production of reactive oxygen species (ROS) and nuclear fragmentation over esophageal, gastric, colorectal, liver and pancreatic cancers. Additionally, PDs can inhibit neovascularization, invasion and metastasis in a dose-dependent manner. Moreover, they can induce chemosensibilization to 5-fluorouracil and cisplatin and can act synergistically with anti-neoplastic drugs such as gemcitabine, paclitaxel and oxaliplatin. All anti-cancer activities are given by activation or inhibition of pathways such as HDAC1/PTEN/Akt, EGFR/ErbB2/ErbB3, and PI3K/Akt; PI3K-AK-mTOR, HDAC1/PTEN/Akt; Wnt/β-catenin. Further investigations and clinical trials are needed to elucidate all molecular mechanisms involved on anti-cancer activities as well as adverse effects on patients.
Gastrointestinal cancers (GICs) are the most common human tumors worldwide, affecting esophageal, stomach, colorectum, liver, pancreas, and gallbladder tissues (
Mental disorders and substance abuse are at present the leading cause of disability worldwide (
The repurposing potential of PDs has ignited interest in further exploration for treating GICs. The aim of this review is to compile the most recent and relevant information about how psychiatric drugs have been redirected due to their inhibitory potential on carcinogenic processes, such as, growth, proliferation, metastasis and cell survival in GICs (
Thioridazine (THD), an antagonist of the dopamine receptor D2, is a potent anti-anxiety and anti-psychotic that in combination with radiotherapy promotes G0/G1 phase cell cycle arrest by CDK4 and cyclinD1 downregulation on the esophageal squamous cell carcinoma (ESCC) ECA-109 and TE-1 cell lines. It also induces apoptosis upregulating cleaved caspase-3 and 9 as well as Bax, Bak, and p53, and decreasing Bcl-2 and Bcl-xL expression. Besides, this treatment inhibits PI3K-AK-mTOR pathway. On xenograft mouse model, THD/radiotherapy reduces ESCC tumor growth (
Valproic acid (VPA), an anti-epileptic (
Fluoxetine (FLX) is a selective serotonin reuptake inhibitor (SSRI) to treat depression and panic disorder (
THD has cytotoxic effect on Gastric cancer (GC) cell lines NCI-N87 and AGS, inhibiting colony formation ability, and induces nuclear fragmentation and apoptosis in a caspase-dependent manner through downregulation of caspase-9, caspase-8, and caspase-3 precursors. Also,
VPA-treated AGS and SGC-7901 cells repress HDAC1/2 (histone deacetylase) activity and induces autophagy driving to apoptosis through HDAC1/PTEN/Akt signaling pathway inhibition, as well as Bcl-2 and Beclin-1 alterations. VPA treatment on xenograft models have shown significant inhibitory effect on cell growth via autophagy/apoptosis (
Trifluoperazine, an anti-psychotic, inhibits cell viability and proliferation, induces apoptosis and promotes cell arrest at G0/G1 phase by repressing CDK2, CDK4, cyclin D1, cyclin E through the increasing p27 expression on HCT116. Also, this effect has a synergized effect with 5-fluorouracil and Oxaliplatin in CT26 and HCT116 colorectal cancer cells (
THD treatment exhibits anti-tumor effect on CSCs EpCAM+/CD44+ subpopulations isolated from HCT116 through apoptosis induction via mitochondrial pathway since THD promotes upregulation of caspase-3 and Bax and downregulation of Bcl-2 suppressing proliferation and invasion (
Chlorpromazine reduces psychotic symptoms and has a potent anti-tumor activity (
Regarding tricyclic anti-depressants (TCAs), desipramine promotes apoptosis and modulates cell-cycle arrest at G0/G1-phase reducing a dose-dependent S-phase proportion cells in HT29 CRC cell line (
Imipramine also compromises HCT116 cells viability at low concentrations and inhibits lamellipodium formation, cell migration and invasion by affecting fascin1 (
In the case of the SSRI Citalopram, it inhibits migration in HT29 and HCT116 cell lines. Besides, it has anti-proliferative effect on xenograft mouse model as well as in orthotopic mouse model, acting against metastatic progression (
The dopamine inhibitor hydrochloride (IND), the dopamine receptor antagonists chlorpromazine hydrochloride (CPZ), and fluphenazine dihydrochloride (FPZ) are able to increase LC3-II in a dose- and time-dependent manner in HCT116 cells. Moreover, FPZ induces autophagy by mTOR signaling inhibition, meanwhile IND and CPZ induces autophagy in an mTOR-independent manner. However, in this context autophagy does not stimulates apoptosis, rather offers beneficial effects for cell survival in HCT116 treated with IND, CPZ and FPZ (
SSRIs including FLX, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine are associated with a lower risk of hepatocellular carcinoma (HCC) in a dose-dependent manner (
The use of risperidone, quetiapine, and clozapine, have shown reduction of cell viability, cell proliferation, invasion, and induction of apoptosis
Mirtazapine is a novel noradrenergic and specific serotonergic anti-depressant (NaSSA) (
Synergistic effects of PDs and chemotherapeutic agents in GICs.
Trifluoperazine | 5-Fluorouracil |
Viability inhibition of CT26 and HCT116 colorectal cancer cells | ( |
Olanzapine | 5-Fluorouracil |
Cell death in PANC-1 cell after chemosensitization by survivin downregulation | ( |
VPA | Gemcitabine | Low-dose VPA significantly enhances cytotoxicity of pancreatic cancer cells to gemcitabine | ( |
Fluoxetine | Paclitaxel | Fluoxetine-paclitaxel combination exhibits anti-proliferative effect on gastric adeno carcinoma cells by G2/M arrest and increased events in the sub G0/G1 phase | ( |
VPA inhibits cell proliferation and cell attachment to the endothelium on DanG cells and enhances β1 integrin subunits expression such as α4, α5, and α6 (
In the case of the anti-psychotic drugs penfluridol, pimozide, fluspirilene, and promethazine have an antagonist effect on proliferation and induce autophagy by LC3II and p62 upregulation in Panc-1, and MiaPaCa-2 human PDAC cell lines. Also, penfluridol suppress colony and spheroid formation and decreases PRL-induced JAK2 signaling by binding to PRLR.
PDs exhibit side effects that need to be considered (
SSRI anti-depressants: headache, nausea, and sexual dysfunction, as well as several cytochrome P450 drug interaction (
FLX: cardiovascular difficulties, akathisia, dyskinesias, parkinsonian-like syndromes, suicidal preoccupation, “serotonin syndrome” (
FLX and Desipramine offer benefits on quality of life issues in patients with advanced cancer (
TCAs: cardiac conduction abnormalities, anti-cholinergic effects, weight gain and sedation. Specifically, Amitriptyline and Imipramine induce sedation, anti-cholinergic effects, weight gain, sexual dysfunction, sedation, and cardiac effects (
VPA: fatigue, confusion, neuroconstipation, and somnolence (
Trifluoperazine: decreased appetite and induces nausea, insomnia, akathisia, dyskinesias, skin disorders, and tremors including convulsions, as well as, hyperprolactinaemia and galacthorrea (
Chlorpromazine: nausea, drowsiness, and tiredness (
THD and Pimozide: cardiac effects (
Mirtazapine: can induces moderate sedation and appetite stimulation that can enhances patients' wellness (
Olanzapine: decrease chemotherapy side effects as nausea and vomiting in advanced cancer patients (
GICs still rank among the leading causes of cancer related death because of late-stage detection and poor survival following metastasis. Treatments depend on multiple factors and constantly fail. Psychiatric drugs (PDs) are promising as a new generation of cancer chemotherapies due to their anti-neoplastic properties in a plethora of cancer types.
Drug repurposing potential of PDs has been studied for the treatment of GICs founding that these drugs can modulate several cellular processes as cell viability, cell growth, proliferation (cell cycle arrest), apoptosis, autophagy, ROS production, and DNA fragmentation. Besides, PDs can inhibit neovascularization, invasion, and metastasis and effects can be in a dose-dependent manner, such as, VPA, FLX, Pimozide, Desipramine, and Sertraline. Moreover, PDs can induce chemosensibilization as Olanzapine combined with 5-fluorouracil, gemcitabine, and cisplatin induce cell death. In addition, low-dose of VPA enhances cytotoxicity to gemcitabine. FLX also shows anti-proliferative effect in combination with paclitaxel, while, trifluoroperazine exerts viability inhibition when combined with 5-fluorouracil and oxaliplatin.
The modulation of several processes by PDs can be through activation or inhibition of multiple pathways such as HDAC1/PTEN/Akt, EGFR/ErbB2/ErbB3, and PI3K/Akt (VPA); PI3K-AK-mTOR, HDAC1/PTEN/Akt (THD); Wnt/β-catenin (pimozide).
Finally, PDs as repurposed drugs, could be more affordable for patients and could also reduce costs for drugs developers. PDs might improve cancer treatments as well as life quality of patients in long therm. Nevertheless, further investigations and clinical trials are needed to elucidate all molecular mechanisms involved on anti-cancer activities of PDs as well as negative side effects on patients.
MA-F, MA-M, MB, EL-V, and RR-P conceived and designed the content of this review and wrote the paper. CL-C contributed to the final version of the manuscript. All authors contributed to the article and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors acknowledge CONACyT for MA-F (575985) and EL-V (304939) fellowships.