morin and Colorectal-Neoplasms

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. The malignant CRC that undergoes metastasis in the advanced stage is usually refractory to existing chemotherapy and shows a poor prognosis. However, to date, efficient targeted-therapy for metastatic CRC is ill-defined. We tested the hypothesis that combined treatment of flavonoid morin and telomerase inhibitor MST‑312 may reduce the cancer stem cell (CSC) traits. To characterize CSC phenotype, we performed the CD133/CD44 subpopulation profiling, tumorsphere formation assay, cell invasion assay and wound healing assay. We have examined the augmenting effects of the combined treatment of morin and MST‑312 for 5-FU (5-fluorouracil) efficacy in human colorectal cancer. Morin and MST‑312 combined treatment reduced CD133 (+) and CD44 (+) subpopulations in human colorectal and breast cancer cells, respectively. Tumorsphere formation and cell invasiveness were decreased with the morin and MST‑312 combination treatment. Consistent with these data, morin and MST‑312 treatment decreased the wound healing capacity of human breast cancer cells. Stress and apoptosis antibody arrays revealed that there were specific upregulated and downregulated proteins resulting from different treatments. Phosphorylation levels of BAD, p53 and Chk1 were enhanced upon morin/MST‑312 treatments in HT-29 cells, whereas caspase-3 cleavage level and expression of IκBα were downregulated by combined morin/MST‑312 treatment in SW620 cells. Finally, morin and MST‑312 co-treatment further augmented the 5-FU efficacy, chemosensitizing the 5-FU resistant human colorectal cancer cells. Taken together, our study suggests that novel targeted-therapy can be implemented by using flavonoid morin and telomerase inhibitor MST‑312 for improved cancer prognosis.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cell Line, Tumor; Colorectal Neoplasms; Drug Resistance, Neoplasm; Enzyme Inhibitors; Flavonoids; Fluorouracil; HT29 Cells; Humans; Mice; Neoplastic Stem Cells; NIH 3T3 Cells; Phosphorylation; STAT3 Transcription Factor; Telomerase

It is evident based on literature that flavonoids from fruit can safely modulate cancer cell biology and induce apoptosis. Therefore, we investigated the anticancer activity of morin, a flavonoid which is plentiful in twigs of mulberry focusing on apoptosis, and its mechanisms. Morin upregulated the Fas receptor, and activates caspase-8, -9 and -3 in HCT-116 cells. Morin also activates Bid, and induced the loss of mitochondrial membrane potential (MMP, ∆Ψm) with Bax protein activation and cytochrome c release. In addition, morin induced ROS generation which was not blocked by N-acetylcysteine. Morin also suppressed Bcl-2 and cIAP-1, anti-apoptotic proteins, which may contribute to augmentation of morin-triggered apoptosis. As an upstream signaling pathway, suppressed Akt activity by morin was associated to apoptosis. This study suggests that morin induces caspase-dependent apoptosis through extrinsic pathway by upregulating Fas receptor as well as through the intrinsic pathway by modulating Bcl-2 and IAP family members, and ROS generation, and that Akt is the critical upstream signaling that regulates the apoptotic effect of morin in human colon cancer HCT-116 cells.

Topics: Antineoplastic Agents; Apoptosis; Caspases; Colorectal Neoplasms; fas Receptor; Flavonoids; HCT116 Cells; Humans; Inhibitor of Apoptosis Proteins; Membrane Potential, Mitochondrial; Proto-Oncogene Proteins c-bcl-2

The modifying effect of dietary exposure to a flavonoid morin during the initiation and post-initiation phases of azoxymethane (AOM)-initiated colorectal carcinogenesis was investigated in male F344 rats. A total of 55 animals were initiated with AOM by weekly s. c. injections of 15 mg/kg body wt for 3 weeks to induce colorectal neoplasms. Rats were fed a diet containing 500 p.p.m. morin for 5 ('initiation feeding') or 28 ('post-initiation feeding') weeks. Other groups contained rats treated with morin alone (500 p.p.m. in diet) and untreated rats. At the end of the study (32 weeks), the incidence of adenocarcinoma in the large intestine of rats initiated with AOM together with (43%) or followed by (29%) a diet containing morin was smaller than that of rats given AOM alone (75%). A significant difference was found between 'post-initiation feeding' and untreated groups (P = 0.023). Although both 'initiation feeding' and 'post-initiation feeding' of morin reduced polyamine levels in colorectal mucosa and blood, 'post-initiation feeding' of morin significantly decreased the proliferating cell nuclear antigen-positive index in aberrant crypt foci. 'Post-initiation feeding' of morin significantly elevated glutathione S-transferase and quinone reductase activities in the liver and large bowel, but 'initiation feeding' caused a significant elevation of these enzymes activities only in the large bowel. These results indicate that morin could exert a weak chemopreventive effect on large bowel tumorigenesis induced by AOM when fed during the post-initiation phase.

Topics: Adenocarcinoma; Adenoma; Animals; Anticarcinogenic Agents; Antioxidants; Azoxymethane; Carcinogens; Colorectal Neoplasms; Drug Screening Assays, Antitumor; Flavonoids; Glutathione Transferase; Male; Polyamines; Precancerous Conditions; Rats; Rats, Inbred F344