Chemoprevention of Prostate Cancer by <scp>d</scp>,<scp>l</scp>-Sulforaphane Is Augmented by Pharmacological Inhibition of Autophagy

Vyas, Avani R.; Hahm, Eun Ryeong; Arlotti, Julie A.; Watkins, Simon C.; Stolz, Donna B.; Desai, Dhimant; Amin, Shantu; Singh, Shivendra V.

doi:10.1158/0008-5472.can-13-0755

Cited by 47 publications

(57 citation statements)

References 51 publications

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“…It has previously been reported that the combination of SFN with autophagy inhibition, by 3-MA or bafilomycin A1, may be a promising strategy for breast cancer (29), human colon cancer (30) or human prostate cancer (8) therapy. Furthermore, the chemopreventive efficacy of SFN may be augmented by inhibition of autophagy using chloroquine in a transgenic adenocarcinoma of mouse prostate as shown in an in vivo study (31). The present study showed that the inhibition of autophagy by 3-MA does not alter …”

Section: A B Csupporting

confidence: 54%

Inhibition of autophagy by 3-methyladenine potentiates sulforaphane-induced cell death of BE(2)-C human neuroblastoma cells

Horwacik¹,

Gaik²,

Durbas³

et al. 2012

Molecular Medicine Reports

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Sulforaphane (SFN) is an isothiocyanate present in cruciferous vegetables, which has been shown to exert an anti-cancer effect when tested in vitro and in vivo. The anti-cancer effects of SFN encompass induction of cytoprotective autophagy; therefore, the present study aimed to determine whether the chemopreventive activity of SFN may be potentiated by inhibition of autophagy. The present study provided detailed insight into the susceptibility of human neuroblastoma cells to treatment with synthetic SFN, in combination with an inhibitor of autophagy, 3-methyladenine (3-MA). The present study confirmed the suppression of the viability of the human neuroblastoma cell line BE(2)-C by SFN and reported the inhibition of DNA synthesis, as determined by a decrease in tritiated thymidine incorporation. Furthermore, the results verified the effectiveness of SFN in inducing apoptosis in the BE(2)-C cell line as demonstrated by caspase activation, increased protein expression levels of B-cell lymphoma 2-associated X protein and loss of mitochondrial membrane potential. Combined treatment of the cells with SFN with 3-MA proved to be effective in decreasing cell viability, through a mechanism that may proceed via the early induction of autophagy by SFN, followed by induction of apoptosis, as well as inhibition of autophagy by 3-MA.

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Section: A B Csupporting

confidence: 54%

Inhibition of autophagy by 3-methyladenine potentiates sulforaphane-induced cell death of BE(2)-C human neuroblastoma cells

Horwacik¹,

Gaik²,

Durbas³

et al. 2012

Molecular Medicine Reports

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“…SFN can downregulate the expression of β-catenin through activation of caspase-3 in human cervical carcinoma HeLa and hepatocarcinoma HepG2 cells. The combination of SFN and chloroquine significantly reduce the incidence as well as size of lymph node metastasis by inhibiting EMT and suppressing proangiogenic cytokine vEGF in prostate cancer compared with control group (22). SFN counteracts aggressiveness of pancreatic cancer driven by dysregulated Cx43-mediated gap junctional intercellular communication (47).…”

Section: Discussionmentioning

confidence: 99%

“…Sulforaphane (SFN), a naturally-occurring member of the isothiocyanate (ITC) family, is ample in normally consumed cruciferous vegetables (22,23). Recently, evidence from numerous epidemiological investigations demonstrated that the higher dietary intakes of cruciferous vegetables were associated with reduced risk of various cancers, such as mammary gland tumorigenesis, colonic aberrant crypt foci, stomach tumors, prostate, bladder and lung cancer (24).…”

Section: Introductionmentioning

confidence: 99%

Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

Lan

Yang

Han

et al. 2015

International Journal of Oncology

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Abstract. The survival benefits of patients with glioblastoma (GBM) remain unsatisfactory due to the intrinsic or acquired resistance to temozolomide (TMZ). We elucidated the mechanisms of sulforaphane (SFN) reverse TMZ resistance in TMZ-inducing cell lines by inhibiting nuclear factor-κB (NF-κB) transcriptional activity. TMZ-resistant cell lines (U87-R and U373-R) were generated by stepwise (6 months) exposure of parental cells to TMZ. Luciferase reporter assay, biochemical assays and subcutaneous tumor establishment were used to characterize the antitumor effect of SFN. MGMT expression and 50% inhibiting concentration (IC 50 ) values of TMZ in GBM cell lines were assessed. Next, we established that U87-R and U373-R cells presenting high IC 50 of TMZ, activated NF-κB transcription and significantly increased MGMT expression compared with untreated cells. Furthermore, we revealed that SFN could significantly suppress proliferation of TMZ-resistant GBM cells. In addition, SFN effectively inhibited activity of NF-κB signaling pathway and then reduced MGMT expression to reverse the chemo-resistance to TMZ in T98G, U87-R and U373-R cell lines. Sequential combination with TMZ synergistically inhibited survival capability and increased the induction of apoptosis in TMZ-resistant GBM cells. Finally, a nude mouse model was established with U373-R cell subcutaneous tumor-bearing mice, and results showed that SFN could remarkably suppress cell growth and enhance cell death in chemo-resistant xenografts in the nude mouse model. Collectively, the present study suggests that the clinical efficacy of TMZ-based chemotherapy in TMZ-resistant GBM may be improved by combination with SFN.

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“…Prostate adenocarcinoma remains a leading cause of cancer mortality among American men despite a comprehensive understanding of the underlying biology, genomic landscape, and the risk factors (9-12). Population-based evidence prompted us to test the efficacy of PEITC and SFN for prevention of prostate cancer using a transgenic mouse model (Transgenic Adenocarcinoma of Mouse Prostate; TRAMP) (13-15). Dietary administration of PEITC (3 μmol/g diet) for 19 weeks to male TRAMP mice resulted in a statistically significant decrease in the incidence of poorly-differentiated prostate cancer when compared to mice fed with basal diet (13).…”

Section: Introductionmentioning

confidence: 99%

CXCR4 Is a Novel Target of Cancer Chemopreventative Isothiocyanates in Prostate Cancer Cells

Sakao

Vyas

Chinni

et al. 2015

Cancer Prevention Research

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Isothiocyanates (ITCs) derived from cruciferous vegetables, including phenethyl isothiocyanate (PEITC) and sulforaphane (SFN), exhibit in vivo activity against prostate cancer in xenograft and transgenic mouse model, and thus are appealing for chemoprevention of this disease. Watercress constituent PEITC and SFN-rich broccoli sprout extract are under clinical investigations but the molecular mechanisms underlying their cancer chemopreventive effects are not fully understood. The present study demonstrates that chemokine receptor CXCR4 is a novel target of ITCs in prostate cancer cells. Exposure of prostate cancer cells (LNCaP, 22Rv1, C4-2, and PC-3) to pharmacologically applicable concentrations of PEITC, benzyl isothiocyanate (BITC), and SFN (2.5 and 5 μmol/L) resulted in downregulation of CXCR4 expression. None of the isothiocyanates affected secretion of CXCR4 ligand (stromal-derived factor-1). In vivo inhibition of PC-3 xenograft growth upon PEITC treatment was associated with a significant decrease in CXCR4 protein level. A similar trend was discernible in the tumors from SFN-treated TRAMP mice compared with those of control mice, but the difference was not significant. Stable overexpression of CXCR4 in PC-3 cells conferred significant protection against wound healing, cell migration, and cell viability inhibition by ITCs. Inhibition of cell migration resulting from PEITC and BITC exposure was significantly augmented by RNA interference of CXCR4. This study demonstrates, for the first time, that cancer chemopreventive ITCs suppress CXCR4 expression in prostate cancer cells in vitro as well as in vivo. These results suggest that CXCR4 downregulation may be an important pharmacodynamic biomarker of cancer chemopreventative ITCs in prostate adenocarcinoma.

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Chemoprevention of Prostate Cancer by d,l-Sulforaphane Is Augmented by Pharmacological Inhibition of Autophagy

Cited by 47 publications

References 51 publications

Inhibition of autophagy by 3-methyladenine potentiates sulforaphane-induced cell death of BE(2)-C human neuroblastoma cells

Inhibition of autophagy by 3-methyladenine potentiates sulforaphane-induced cell death of BE(2)-C human neuroblastoma cells

Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

CXCR4 Is a Novel Target of Cancer Chemopreventative Isothiocyanates in Prostate Cancer Cells

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