Didox and resveratrol sensitize colorectal cancer cells to doxorubicin via activating apoptosis and ameliorating P-glycoprotein activity

Abstract

Doxorubicin (DOX) has limited efficacy in colorectal cancer due to multi-drug resistance. Resveratrol (RES) and didox (DID) are polyhydroxyphenols with potential chemosensitizing effects. Herein, we assessed the chemomodulatory effects of RES and DID to DOX in colorectal cancer cells. Equitoxic combination of DOX with RES and DID in HCT 116 reduced the IC50 of DOX from 0.96 ± 0.02 μM to 0.52 ± 0.05 μM and 0.4 ± 0.06 μM, respectively. Similarly, combination of DOX with RES and DID in HT-29 decreased the IC50’s of DOX from 0.88 ± 0.03 μM to 0.47 ± 0.02 μM and 0.29 ± 0.04 μM, respectively. The expressions of p53 and Bax genes were markedly elevated in HCT 116 cells after exposure to DOX/DID. In HT-29 cells, the expression of Bcl-XL gene was significantly decreased after exposure to DOX/DID. In addition, combination of DOX with RES significantly increased the expression of Bax gene in HCT 116 cells. RES treatment induced significant S-phase arrest in DOX-treated HCT 116 cells, while DID induced G2/M- and S-phase arrest in HCT 116 and HT-29, respectively. Both RES and DID significantly enhanced the intracellular entrapment of DOX due to blocking the efflux activity of p-glycoprotein pump. In conclusion, RES and DID sensitize colorectal cancer cells to DOX via facilitating apoptosis and enhancing intracellular entrapment of DOX.

Alleviation of Multidrug Resistance by Flavonoid and Non-Flavonoid Compounds in Breast, Lung, Colorectal and Prostate Cancer

“…Nevertheless, based on reported data, some polyphenols can target the same molecule in different cancer cell lines. For instance, resveratrol can downregulate P-gp in breast, lung and colorectal cancer cells [210][211][212]. Taken together these data suggest that polyphenols are able to modulate different signaling pathways being cell-line-specific and to target certain molecules independent of cell type (Table 2).…”

“…Resveratrol is a polyphenol commonly found in red wine and grapes that possesses strong antioxidant and anti-aging properties [209]. According to several studies co-administration of resveratrol and other therapeutic agents (paclitaxel, docetaxel, doxorubicin, rapamycin, gefitinib) reversed MDR in breast, lung and colorectal cancer through enhancement of chemotherapeutic agents bioavailability, increase drug retention time, stimulation of pro-apoptosis mechanisms, cell cycle arrest or downregulation of ABC transporters [209][210][211][212][213][214].…”

Restoring Treatment Response in Colorectal Cancer Cells by Targeting MACC1-Dependent ABCB1 Expression in Combination Therapy

“…In the case of CRC, upregulation of ABC transporters with broad substrate specificity during therapy critically limits the use of common and effective cytotoxic drugs like anthracyclines (27). To meet the clinical need to overcome multi-drug resistance, current research concentrates on small molecules, either natural or synthetic compounds, which can functionally inhibit ABC transporters or reduce their induction under therapy (28)(29)(30)(31)(32)(33). In addition, the focus on approved drugs in overcoming multi-drug resistance allows the fast translation of novel treatment strategies into the clinics.…”

Reduction of Hepatotoxicity Induced by Doxorubicin

“…Most recent and significative studies are summarized in Table 3. RSV sensitized colorectal [118] and breast [119] cancer cells to DO x via facilitating apoptosis and enhancing intracellular entrapment of DO x and through inhibiting breast cancer cells proliferation and invasion, respectively. DO x -induced either injuries [120] or apoptosis [121] H9c2 cardiac cells were protected by RSV via sirtuin 1 (SIRT1) activation and the AMPK/P53 pathway, respectively.…”