Abstract
Adriamycin (ADR) is a chemotherapeutic drug widely utilized to treat multiple types of cancers; however, the clinical efficacy of ADR is compromised due to the development of drug resistance in patients. The combination of drugs with ADR may provide a better therapeutic regimen to overcome this obstacle. Glutaminase (GLS) has been explored as a therapeutic cancer target, and its inhibition also results in increased sensitivity of tumor cells to chemotherapeutic agents. This study aimed to investigate whether GLS inhibition could reverse ADR resistance. We treated the ADR-resistant MCF-7 (MCF-7ADR) cells with a GLS inhibitor, compound 968 or CB-839, in combination with ADR. We found that compound 968, rather than CB-839, together with ADR synergistically inhibited the cell viability. These results indicated that compound 968 reversed ADR resistance in MCF-7ADR cells independently of GLS. Moreover, we modified the structure of compound 968 and finally obtained a compound 968 derivative, SY-1320, which was more potent than compound 968 in eliminating the drug resistance in MCF-7ADR cells. Furthermore, using drug affinity responsive target stability and streptavidin–biotin immunoprecipitation assays, we demonstrated that SY-1320 could specifically target P-glycoprotein (P-gp) and increase ADR accumulation through inhibition of P-gp, thereby resulting in cell death in MCF-7ADR cells. Together, our findings indicate that compound 968 or SY-1320 might be a promising drug for new combination chemotherapy in breast cancer to overcome the drug resistance.
Highlights
Breast cancer, which has high mortality rates, is a frequently occurring cancer in women [1]
Increased expression of P-glycoprotein (P-gp), which is encoded by ATP-binding cassette subfamily B member 1 (ABCB1) gene, often contributes to ADR resistance in cancer [9, 10]
We found that a combination of ADR and compound 968, rather than CB-839, led to synergistic tumor cell death in MCF-7ADR cells, suggesting that compound 968 might reverse ADR resistance independently of GLS
Summary
Breast cancer, which has high mortality rates, is a frequently occurring cancer in women [1]. For early-stage breast cancer, surgical treatment has good therapeutic effects, while chemotherapy can significantly improve the 5-year survival rate of patients with middle- or advanced-stage breast cancer [2]. Adriamycin (ADR) has been shown to have well-established benefits for these patients [3, 4]. Despite its success in improving cancer survival rates, long-term ADR treatment may lead to drug resistance and side effects [7, 8]. Increased expression of P-glycoprotein (P-gp), which is encoded by ATP-binding cassette subfamily B member 1 (ABCB1) gene, often contributes to ADR resistance in cancer [9, 10]. Many clinical trials using P-gp inhibitors are being evaluated, but the inhibitor toxicities or drug interactions drive researchers to develop more rational inhibitors [11,12,13]
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