Autophagy inhibition improves the chemotherapeutic efficacy of cruciferous vegetable-derived diindolymethane in a murine prostate cancer xenograft model
Prostate cancer is the second leading cause of cancer-related deaths in men in North America and there is an urgent need for development of more effective therapeutic treatments against this disease. We have recently shown that diindolylmethane (DIM) and several of its halogenated derivatives (ring-DIMs) induce death and protective autophagy in human prostate cancer cells. However, the in vivo efficacy of ring-DIMs and the use of autophagy inhibitors as adjuvant therapy have not yet been studied in vivo. The objective of this study was to determine these effects on tumor growth in nude CD-1 mice bearing bioluminescent androgen-independent PC-3 human prostate cancer cells. We found that chloroquine (CQ) significantly sensitized PC-3 cells to death in the presence of sub-toxic concentrations of DIM or 4,4'-Br2DIM in vitro. Moreover, a combination of DIM (10 mg/kg) and CQ (60 mg/kg), 3× per week, significantly decreased PC-3 tumor growth in vivo after 3 and 4 weeks of treatment. Furthermore, 4,4'-Br2DIM at 10 mg/kg (3× per week) significantly inhibited tumour growth after 4 weeks of treatment. Tissues microarray analysis showed that DIM alone or combined with CQ induced apoptosis marker TUNEL; the combination also significantly inhibited the cell proliferation marker Ki67. In conclusion, we have confirmed that DIM and 4,4'-Br2DIM are effective agents against prostate cancer in vivo and shown that inhibition of autophagy with CQ enhances the anticancer efficacy of DIM. Our results suggest that including selective autophagy inhibitors as adjuvants may improve the efficacy of existing and novel drug therapies against prostate cancer.
KeywordsProstate cancer PC-3 CD-1 nude mice Autophagy Diindolylmethane Ring-DIMs
This work was supported by an operating grant from the Canadian Institutes of Health Research (CIHR grant no. MOP-115019) to Thomas Sanderson and Emma Guns. Hossam Draz received a scholarship from the Fonds de Recherche du Québec - Santé (FRQS).
Compliance with ethical standards
Conflict of interest
Hossam Draz, Alexander Goldberg, Emma Guns, Ladan Fazli, Stephen Safe and Thomas Sanderson each declare to have no conflicts of interest.
All applicable international, national and institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the Centre National de Biologie Expérimentale where the studies were conducted. This article does not contain any studies with human participants performed by any of the authors.
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