Nrf2 is a key factor in the reversal effect of curcumin on multidrug resistance in the HCT‑8/5‑Fu human colorectal cancer cell line

Abstract

Multidrug resistance (MDR) is a major concern when using chemotherapy for the treatment of patients with colorectal cancer. MDR modulators are agents that can reverse MDR and, thus, enhance the chemosensitivity of tumor cells. The development of MDR modulators can improve the therapeutic efficacies of MDR in cancer. However, few effective MDR modulators have been identified so far. Curcumin has been reported to be an effective compound in the reversal of MDR in colorectal cancer cells. However, the mechanisms associated with the reversal effect of curcumin on MDR and its regulation of target factors in MDR cells remain to be fully elucidated. 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyltetrazolium bromide assays, flow cytometer apoptosis assays as well as mRNA and protein expression assays were performed in the present study, and the results confirmed the reversal effect of curcumin on HCT-8/5-Fu cells and provided evidence that activated nuclear factor erythroid 2-related factor (Nrf2) deficiency induced by the curcumin altered the B-cell lymphoma 2 (Bcl-2) associated X protein/Bcl-2 expression ratio, which led to the induction of apoptosis in HCT-8/5-Fu cells. These results indicated that Nrf2 may have a functional in the reversal effect of curcumin and contribute, at least in part, to the outcomes of chemotherapy in patients with MDR.

The Effect of Compound Sophora on Fluorouracil and Oxaliplatin Resistance in Colorectal Cancer Cells

“…Chemotherapy is an important means of treating colorectal cancer, but many patients show MDR during the course of chemotherapy, which is the main reason for treatment failure [3,4]. Chemotherapy for colorectal cancer consists mostly of three drugs, 5-FU, oxaliplatin.…”

“…MDR (also known as multidrug hold) occurs when a tumour cell develops antitumour drug resistance, in which different chemical structures exert different actions. Different antitumour drugs also produce cross-resistance [3,4]. Abnormal expression of drug-resistance proteins such as permeability glycoprotein (P-gp), annexin A1 (ANXA1), and ATP-binding cassette superfamily G member 2 (ABCG2) have been found in colorectal tumour tissues of patients with primary MDR, resulting in different levels of drug resistance to chemotherapy drugs in tumour cells [5][6][7].…”

The Implication of a Novel Herbal Formulation in Reversal of Drug-Resistance for Cancer Treatment

“…IC 50 value determines the concentration of drug at which 50% of cells survive. Drug Resistance Index (DRI) of 5FU on HeLa-R cells was calculated using the formula: IC 50 of resistant cells/ IC 50 of sensitive cells (41).…”

Can Nrf2 Modulate the Development of Intestinal Fibrosis and Cancer in Inflammatory Bowel Disease?

“…Zhang et al demonstrated that curcumin was involved in MDR in colorectal cancer cell lines through a direct link with Nrf2. In fact, this compound, in combination with 5-FU, was able to induce apoptosis and reduce Nrf2 and Bcl-2/Bax expression, leading to a reversal effect on MDR in colon cancer [152]. Recently, Zhang et al revealed, for the first time, the involvement of DUB3—an alternative Nrf2 deubiquitinating enzyme—in chemoresistance occurring in colorectal cancer.…”