Genistein enhances the efficacy of cabazitaxel chemotherapy in metastatic castration-resistant prostate cancer cells

Zhang, Shumin; Wang, Yanru; Chen, Zhengjia; Kim, Sungjin; Iqbal, Shareen; Chi, Andrew; Ritenour, Chad W.M.; Wang, Yongqiang A.; Küçük, Ömer; Wu, Daqing

doi:10.1002/pros.22705

Cited by 23 publications

(33 citation statements)

References 38 publications

(45 reference statements)

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“…In the present study we investigated whether physiologically attainable concentrations of soy isoflavones could act synergistically with taxanes to induce growth inhibition of clinically relevant CRPC cell lines in vitro and in vivo; speculated that daidzein and equol may also exhibit synergistic effects with taxanes due to similarities with genistein in their activity and structures; and explored effects of soy isoflavones on the chemotherapeutic mechanism of taxanes and the mechanisms of taxane resistance. Contrary to published reports, some recommended for retraction, we did not find evidence that genistein synergistically enhanced the efficacy of taxanes or affected taxane mechanisms.…”

Section: Introductioncontrasting

confidence: 99%

“…Only few experimental studies have addressed the possible benefits or harm of genistein in combination with chemotherapy for CRPC, one of which indicated the potential of genistein to enhance taxane efficacy in preclinical xenograft models using PC‐3 cells and in vitro in two other CRPC cell lines with high genistein doses . Some other papers with similar findings were recommended by the author's institution to be retracted because of image manipulation.…”

Section: Introductionmentioning

confidence: 99%

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Lack of combination effects of soy isoflavones and taxane chemotherapy of castration‐resistant prostate cancer

2018

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Background Patients with cancer, including prostate cancer, often use dietary supplements, such as soy or isoflavones, before, during, or after therapy. There is little information about possible interactions between supplements and cancer chemotherapy. There are some reports suggesting enhancement by genistein of taxane chemotherapy for castrate‐resistant prostate cancer (CRPC). Methods We investigated whether physiologically attainable concentrations of soy isoflavones (≤10 μM) interact with taxanes on growth inhibition of CRPC cells in vitro and in vivo in nude mice exposed via the diet, on microtubule disassembly in vitro, and on P‐glycoprotein‐mediated drug efflux in 22Rv1 cells and CYP3A4 activity in microsomes. Results Genistein, daidzein, and equol did not affect growth of VCaP, 22Rv1, C4‐2, and PC‐3 CRPC cells or growth inhibition of these cells by docetaxel and cabazitaxel. These isoflavones did not inhibit microtubule disassembly in vitro or inhibit the microtubule effects of taxanes and genistein did not bind substantially to microtubules. Genistein considerably inhibited P‐glycoprotein‐mediated drug efflux in 22Rv1 cells and CYP3A4 activity in microsomes. However, dietary supplementation with genistein at 250 and 500 ppm did not affect the tumor growth inhibiting effect of docetaxel on 22Rv1 cells xenografted in nude mice. Conclusions Our results with relevant cell models and clinically achievable concentrations of soy isoflavones do not support the notion that genistein or other soy isoflavones can enhance the effects of taxane chemotherapy in CRPC cell and xenograft models. Yet, the inhibitory effects of genistein on drug efflux in 22Rv1 cells and on microsomal CYP3A4 activity raise the possibility that genistein can affect taxane effects on CRPC cells in other circumstances than those we studied, which merits further research.

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Section: Introductioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Lack of combination effects of soy isoflavones and taxane chemotherapy of castration‐resistant prostate cancer

2018

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“…Combination chemotherapy has several advantages such as lower dose requirement which subsequently lessens the side effects and circumvents drug resistance; and inhibits or delays metastasis (12–18). Zhang et al (13) showed that genistein enhances the response to cabazitaxel treatment in mCRPC cells. Synergistic drug interactions act in concert to reduce long term colonogenic survival and inhibit oncogenic and metastatic pathways (19–21).…”

Section: Introductionmentioning

confidence: 99%

Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells

Mukhtar

Adhami

Siddiqui

et al. 2016

Molecular Cancer Therapeutics

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Although treatment of prostate cancer (PCa) has improved over the past several years, taxanes such as cabazitaxel remain the only form of effective chemotherapy that improves survival in patients with metastatic castration-resistant PCa. However, the effectiveness of this class of drugs has been associated with various side effects and drug resistance. We previously reported that fisetin, a hydroxyflavone, is a microtubule stabilizing agent and inhibits PCa cell proliferation, migration, and invasion and suggested its use as an adjuvant for treatment of prostate and other cancer types. In this study, we investigated the effect of fisetin in combination with cabazitaxel with the objective to achieve maximum therapeutic benefit, reduce dose and toxicity and minimize or delay the induction of drug resistance and metastasis. Our data show for the first time that a combination of fisetin (20 μM) enhances cabazitaxel (5nM) and synergistically reduces 22Rν1, PC-3M-luc-6, and C4-2 cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. In addition, the combination of fisetin with cabazitaxel was associated with inhibition of proliferation and enhancement of apoptosis. Furthermore, combination treatment resulted in inhibition of tumor growth, invasion and metastasis when assessed in two in-vivo xenograft mouse models. These results provide evidence that fisetin may have therapeutic benefit for patients with advanced PCa through enhancing the efficacy of cabazitaxel under both androgen-dependent and androgen-independent conditions. This study underscores the benefit of the combination of fisetin with cabazitaxel for the treatment of advanced and resistant PCa and possibly other cancer types.

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“…Options for patients with advanced stage disease are limited. The standard of care for metastatic prostate cancer patients is chemical castration, a hormone therapy that reduces androgen levels and removes necessary growth components for transformed prostate cancer cells, halting cell growth (4,5). Alternatively, hormone manipulation can be avoided when treating advanced prostate cancer with personalized therapeutic treatments such as Sipuleucel-T (Provenge®), which activates the immune system to attack cells expressing tumor associated antigens (TAA) (6).…”

Section: Introductionmentioning

confidence: 99%

Forced LIGHT expression in prostate tumors overcomes Treg mediated immunosuppression and synergizes with a prostate tumor therapeutic vaccine by recruiting effector T lymphocytes

et al. 2014

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Background LIGHT, a ligand for lymphotoxin-β receptor (LTβR) and herpes virus entry mediator, is predominantly expressed on activated immune cells and LTβR signaling leads to the recruitment of lymphocytes. The interaction between LIGHT and LTβR has been previously shown in a virus induced tumor model to activate immune cells and result in tumor regression, but the role of LIGHT in tumor immunosuppression or in a prostate cancer setting, where self antigens exist, has not been explored. We hypothesized that forced expression of LIGHT in prostate tumors would shift the pattern of immune cell infiltration, would inhibit T regulatory cells (Tregs) and would induce prostate cancer tumor associated antigen (TAA) specific T cells that would eradicate tumors. Methods Real Time PCR was used to evaluate expression of forced LIGHT and various other genes in prostate tumors samples. Adenovirus encoding murine LIGHT was injected intratumorally into TRAMP C2 prostate cancer cell tumor bearing mice for in vivo studies. Chemokine and cytokine concentrations were determined by multiplex ELISA. Flow cytometry was used to phenotype tumor infiltrating lymphocytes and expression of LIGHT on the tumor cell surface. Tumor specific lymphocytes were quantified via an ELISpot assay. Treg induction and Treg suppression assays determined Treg functionality after LIGHT treatment. Results LIGHT expression peaked within 48 hours of infection, recruited effector T cells into the tumor microenvironment that recognized mouse prostate stem cell antigen (PSCA) and inhibited the infiltration of Tregs. Tregs isolated from tumor draining lymph nodes had impaired suppressive capability after LIGHT treatment. LIGHT in combination with a therapeutic vaccine, PSCA TriVax, reduced tumor burden. Conclusion Forced LIGHT treatment combined with PSCA TriVax therapeutic vaccination delays prostate cancer progression in mice by recruiting effector T lymphocytes to the tumor and inhibiting Treg mediated immunosuppression.

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Genistein enhances the efficacy of cabazitaxel chemotherapy in metastatic castration-resistant prostate cancer cells

Cited by 23 publications

References 38 publications

Lack of combination effects of soy isoflavones and taxane chemotherapy of castration‐resistant prostate cancer

Lack of combination effects of soy isoflavones and taxane chemotherapy of castration‐resistant prostate cancer

Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells

Forced LIGHT expression in prostate tumors overcomes Treg mediated immunosuppression and synergizes with a prostate tumor therapeutic vaccine by recruiting effector T lymphocytes

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