Autophagy inhibition improves the chemotherapeutic efficacy of cruciferous vegetable-derived diindolymethane in a murine prostate cancer xenograft model

Abstract

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'-BrDIM 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'-BrDIM 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'-BrDIM 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.

Chloroquine-Induced DNA Damage Synergizes with Nonhomologous End Joining Inhibition to Cause Ovarian Cancer Cell Cytotoxicity

“…CQ, an antimalarial and anti-inflammatory drug, is one of the most prominent cases of drug repurposing in cancer [ 59 ]. Several reports and clinical trials have revealed the benefit of combining this compound with different chemotherapeutic drugs [ 9 , 11 , 12 , 13 , 14 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. In this study, we describe a synergistic effect between CQ and NHEJ inhibitors for the first time.…”

“…In addition, CQ is considered a potential anticancer agent; it has been described to reduce hypoxia, cancer cell invasion, and metastasis [ 10 ]. Moreover, several preclinical results and clinical trials have shown that this compound, in combination with other antitumor drugs, increases the cytotoxic effect and sensitizes tumor cells to radiotherapy or chemotherapy [ 9 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. The effect of CQ as an anticancer drug has been mainly attributed to autophagy inhibition [ 9 , 12 , 13 , 14 , 21 , 22 , 23 ], a process that promotes cancer cell survival by recycling intracellular organelles and proteins [ 11 , 24 , 25 , 26 ], and it is considered a resistance mechanism against chemotherapy [ 27 ].…”

Silencing of FTX suppresses pancreatic cancer cell proliferation and invasion by upregulating miR-513b-5p

“…Xenotransplantation model is an ideal animal model for tumor research [51,52]. At present, xenografted mouse models have been established for PC, gastric cancer, breast cancer and other tumors, which maintained the pathological and histological characteristics of the original tumor from multiple perspectives such as histopathology and genetics [53][54][55][56]. In this study, the effects of FTX on PC tumor growth in vivo were investigated by establishing xenotransplantation mouse model.…”

Research Trend and Detailed Insights into the Molecular Mechanisms of Food Bioactive Compounds against Cancer: A Comprehensive Review with Special Emphasis on Probiotics

“…Also, CQ treatment led to increased sensitization of prostate cancer cells to DIM treatment. Thus, DIM and CQ acted synergistically to inhibit prostate cancer [ 253 ].…”