Can diallyl trisulfide, a dietary garlic-derived compound, activate ferroptosis to overcome therapy resistance in prostate cancer?

BACKGROUND: Therapy resistance is the underlying reason for poor outcome in prostate cancer (PCa) patients. Diallyl trisulfide (DATS) is an organosulfur compound present in garlic. DATS has been shown to target PCa cells by induction of apoptosis, increase in the production of reactive oxygen species, degradation of ferritin protein and increase in the labile iron (Fe) pool. AIM: We hypothesize that DATS could induce ferroptosis, an Fe-dependent, unique non-apoptotic form of regulated cell death to eliminate therapy resistance encountered by PCa patients. METHODS: In vitro and in vivo studies should be performed to test the hypothesis. RESULTS: As per the hypothesis, DATS would eliminate apoptotic resistance via inducing ferroptosis. CONCLUSION: Since apoptosis resistance has been reported to be the underlying mechanism of therapy resistance in PCa, DATS could be used to effectively target PCa cells by overcoming apoptosis resistance and inducing ferroptosis-mediated cell death of PCa cells.

Eprinomectin, a novel semi-synthetic macrocylic lactone is cytotoxic to PC3 metastatic prostate cancer cells via inducing apoptosis.

Prostate Cancer (PCa) is the second most common cancer among men in United States after skin cancer. Conventional chemotherapeutic drugs available for PCa treatment are limited due to toxicity and resistance issues. Therefore, there is an urgent need to develop more effective treatment for advanced PCa. In this current study, we focused on evaluating the anti-cancer efficacy of Eprinomectin (EP), a novel avermectin analog against PC3 metastatic PCa cells. EP displayed robust inhibition of cell viability of PC3 cells in addition to suppressing the colony formation and wound healing capabilities. Our study showed that EP targets PC3 cells via inducing ROS and apoptosis activation. EP treatment enforces cell cycle arrest at G0/G1 phase via targeting cyclin-dependent kinase 4 (CDK4) and subsequent induction of apoptosis in PC3 cells. At the molecular level, EP effectively inhibited the expression of various cancer stem cell markers such as ALDH1, Sox-2, Nanog, Oct3/4 and CD44. Interestingly, EP also inhibited the activity of alkaline phosphatase, a maker of pluripotent stem cells. Of note, EP treatment resulted in the translocation of ß-catenin from the nucleus to the cytoplasm indicating that EP antagonizes Wnt/ß-catenin signaling pathway. Western blotting analysis revealed that EP downregulated the expression of key cell cycle markers such as cyclin D1, cyclin D3, CDK4, and c-Myc. In addition, EP inhibited the anti-apoptotic markers such as Mcl-1, XIAP, c-IAP1 and survivin in PC3 cells. On the other hand, EP treatment resulted in the activation of pH2A.X, Bad, caspase-9, caspase-3 and cleavage of PARP1. Taken together, our data suggests that EP is a potential agent to treat advanced PCa cells via modulating apoptosis signaling.

Polygodial analog induces apoptosis in LNCaP prostate cancer cells.

Prostate cancer (PCa) is the second leading cause of death in American men. The chemotherapeutic treatment strategies are generally not effective and can lead to side effects. Hence, there is an urgent need to identify novel chemotherapeutic agents. The aim of this study was to synthesize and evaluate the therapeutic effects of a synthetic analog of polygodial (PG), a pungent constituent abundantly present in mountain pepper, water pepper and dorrigo pepper, on LNCaP PCa cell line and its anti-cancer mechanisms in a preclinical study. We evaluated the anti-cancer potential of the PG analog namely DRP-27 using various assays such as cell viability by MTT assay, anchorage independent growth by soft agar assay, reactive oxygen species generation by 2',7'-dichlorofluorescein probe-based fluorescence assay, and apoptosis by Annexin-V and TUNEL assays respectively. Western blot analysis was performed to identify the molecular mechanism of DRP-27-induced cell death. Our results showed that DRP-27 significantly inhibited LNCaP cell proliferation in a dose-dependent manner at 48 h treatment in vitro. In addition, DRP-27 potently inhibited anchorage-independent growth of these cells. Flow cytometry, Annexin-V and TUNEL assays confirmed that DRP-27 induces apoptosis in LNCaP cells. DRP-27 also induced the activation of intracellular reactive oxygen species. Western blot analysis revealed that DRP-27 downregulated the expression of survivin, while activating Bax and DNA damage marker pH2AX in LNCaP cells. In conclusion, our study suggests that DRP-27 might be an effective anti-cancer agent for PCa.

Vitamin K2, a menaquinone present in dairy products targets castration-resistant prostate cancer cell-line by activating apoptosis signaling.

The aim of this study was to evaluate the therapeutic effects of vitamin K2 (VK2) on castration-resistant prostate cancer (CRPC) and its anti-cancer mechanisms in a pre-clinical study using a VCaP cell line (ATCC® CRL-2876™) which was established from a vertebral bone metastasis from a patient with hormone refractory prostate cancer. Our data showed that VK2 significantly inhibited CRPC VCaP cell proliferation in a dose-dependent manner at 48 h treatment in vitro. In addition, VK2 reduced the migration potential of VCaP cells and inhibited anchorage-independent growth of these cells. Our results also showed that VK2 induces apoptosis in VCaP cells. Furthermore, VK2 enforced growth arrest in VCaP cells by activating cellular senescence. Notably, VK2 treatment elevated the levels of reactive oxygen species in VCaP cells. Western blot analysis revealed that VK2 downregulated the expression of androgen receptor, BiP, survivin, while activating caspase-3 and -7, PARP-1 cleavage, p21 and DNA damage response marker, phospho-H2AX in VCaP cells. In conclusion, our study suggests that VK2 might be a potential anti-cancer agent for CRPC by specifically targeting key anti-apoptotic, cell cycle progression and metastasis-promoting signaling molecules.