Abstract
Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide with limited treatment options. Biomarker-based active phenolic flavonoids isolated from medicinal plants might shed some light on potential therapeutics for treating HCC. 3,3′-diindolylmethane (DIM) is a unique biologically active dimer of indole-3-carbinol (I3C), a phytochemical compound derived from Brassica species of cruciferous vegetables—such as broccoli, kale, cabbage, and cauliflower. It has anti-cancer effects on various cancers such as breast cancer, prostate cancer, endometrial cancer, and colon cancer. However, the molecular mechanism of DIM involved in reducing cancer risk and/or enhancing therapy remains unknown. The aim of the present study was to evaluate anti-cancer and therapeutic effects of DIM in human hepatoma cell lines Hep3B and HuhCell proliferation was measured with MTT and trypan blue colony formation assays. Migration, invasion, and apoptosis were measured with Transwell assays and flow cytometry analyses. Reactive oxygen species (ROS) intensity and the loss in mitochondrial membrane potential of Hep3B and Huh7 cells were determined using dihydroethidium (DHE) staining and tetramethylrhodamine ethyl ester dye. Results showed that DIM significantly suppressed HCC cell growth, proliferation, migration, and invasion in a concentration-dependent manner. Furthermore, DIM treatment activated caspase-dependent apoptotic pathway and suppressed epithelial–mesenchymal transition (EMT) via ER stress and unfolded protein response (UPR). Taken together, our results suggest that DIM is a potential anticancer drug for HCC therapy by targeting ER-stress/UPR.
Highlights
In the overall rate of cancer incidence and mortality, Hepatocellular carcinoma (HCC) is the fifth most common form of cancer and the third leading cause of cancer-related death worldwide
We evaluated molecular mechanisms of anti-cancer effects of DIM in two HCC cell lines, Hep3B and HuhOur findings demonstrated that DIM could dosedependently reduce proliferation, invasion, and migration of HCC cells and induce apoptosis by regulating endoplasmic reticulum (ER) stress and mitochondrial dysfunction of HCC cells
G, immunoblot analysis revealed that DIM treatment significantly increased the expression of cleaved caspase-3, cleaved PARP, cleaved caspase-9, an9doBf a2x3, but decreased levels of anti-apoptotic proteins Bcl2 in a concentration-dependent order compared to the control. These results suggest that DIM can induce intrinsic apoptosis via FEiRgu-srtere4sAs-i,Bnd, u40ceμdMmiDtoIcMhoinndcrreiaalsdedysCfuan2+ctiinonboatnhdcseullbslienqeuseanst cceolml dpeaartehdaws ditohwtnhsetrveeahmicolef cRoOntSroinl
Summary
In the overall rate of cancer incidence and mortality, HCC is the fifth most common form of cancer and the third leading cause of cancer-related death worldwide. It is associated with an extremely poor prognosis [1,2]. Due to its strong invasion ability and the complexity of the metastatic process, treatment options for HCC patients are very limited and its prognosis is dire [5,6]. There is a variety of therapeutic options such as chemotherapy, immunotherapy, intravenous drug embolization, and surgery in the treatment of HCC patients [7], many of them remain challenging and ineffective due to cytotoxicity and multidrug resistance. Developing an anticancer drug from plant-derived compounds as potential therapeutics for HCC is urgently needed
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