Combination treatment with flavonoid morin and telomerase inhibitor MST‑312 reduces cancer stem cell traits by targeting STAT3 and telomerase.
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.
Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA.
Seyung S
SS
Chung
Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA.
Bryant
B
Oliva
Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA.
Sami
S
Dwabe
Division of Cancer Research and Training, Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, USA.
Jaydutt V
JV
Vadgama
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005419:Flavonoids / Q000008:administration & dosage / Q000494:pharmacology*; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047309:Flavones
D001549:Benzamides; D004791:Enzyme Inhibitors; D005419:Flavonoids; D005472:Fluorouracil; D050796:STAT3 Transcription Factor; D019098:Telomerase; C470197:MST 312; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C008548:morin; D047309:Flavones