Abstract
Cancer treatment is limited due to the diverse multidrug resistance acquired by cancer cells and the collateral damage caused to adjacent normal cells by chemotherapy. The flavonoid compound vitexin exhibits anti-oxidative, anti-inflammatory and anti-tumor activity. This study elucidated the antitumor effects of vitexin and its underlying mechanisms in a multi-drug resistant human colon cancer cell line (HCT-116DR), which exhibits higher levels of multidrug-resistant protein 1 (MDR1) expression as compared with its parental cell line (HCT-116). Here, we observed that vitexin suppressed MDR-1 expression and activity in HCT-116DR cells and showed cytotoxic effect in HCT-116DR cells by inhibiting autophagy and inducing apoptosis in a concentration-dependent manner. Additionally, vitexin treatment caused cleavage of caspase-9 and caspase-3, and upregulated the expression of the pro-apoptotic proteins, BID and Bax. Moreover, the expression of autophagy-related proteins, such as ATG5, Beclin-1 and LC3-II, was markedly reduced by vitexin treatment. Furthermore, in vivo experiments showed that vitexin induced apoptosis and suppressed tumor growth in HCT-116DR xenograft model. These results revealed that vitexin induced apoptosis through suppression of autophagy in vitro and in vivo and provide insight into the therapeutic potential of vitexin for the treatment of chemo-resistant colorectal cancer.
Highlights
Colon cancer is the third most diagnosed cancer and the leading cause of cancer-related mortalities worldwide
Vitexin-treated cells exhibited increased lactate dehydrogenase (LDH) activity (Figure 1D), suggesting that vitexin inhibited the viability of drug-resistant colorectal cancer cells
We observed that vitexin markedly reduced the cell viability in these cell lines (Supplementary Figure 1), which suggest that vitexin can exert its cytotoxicity against diverse range of cell lines
Summary
Colon cancer is the third most diagnosed cancer and the leading cause of cancer-related mortalities worldwide. Some colon cancer patients fail to respond to conventional treatment due to resistance acquired by cancer cells against structurally and mechanistically unrelated compounds known as multi drug resistance (MDR), which causes recurrent tumor progression [2]. Most research is streamlined for the development of natural anticancer agents that possess low toxicity and overcome MDR phenotypes to decrease limitations associated with the cure rate and probable survival of cancer patients. One of the mechanisms of MDR is associated with the active extrusion of antineoplastic agents from cancer cells through transporter proteins, which reduces the intracellular concentration of www.impactjournals.com/oncotarget the drug below the cytotoxic threshold [3]. Drug efflux from cancer cells is tightly regulated by ATP binding cassette (ABC) transporter family proteins. High level expression of ABC proteins is observed in various human cancers and results in development of resistance to multiple anti-cancer drugs [4]
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