Abstract
Overexpression of drug efflux transport ABCB1 is correlated with multidrug resistance (MDR) among cancer cells. Upregulation of ABCB1 accounts for the recurrence of resistance to docetaxel therapy in ovarian cancer with poor survival. Erastin is a novel and specific small molecule that targets SLC7A11 to induce ferroptosis. In the present research, we explored the synergistic effect of erastin and docetaxel in ovarian cancer. We confirmed that the co-delivery of erastin with docetaxel significantly decreased cell viability, promoted cell apoptosis, and induced cell cycle arrest at G2/M in ovarian cancer cells with ABCB1 overexpression. Mechanistically, erastin dominantly elevated the intracellular ABCB1 substrate levels by restricting the drug-efflux activity of ABCB1 without alteration of the expression of ABCB1. Consequently, erastin can reverse ABCB1-mediated docetaxel resistance in ovarian cancer, revealing that the combination of erastin and docetaxel may potentially offer an effective administration for chemo-resistant patients suffering from ovarian cancers.
Highlights
Ovarian cancer threatens women’s health with high morbidity and mortality and is the leading cause of death in gynecological malignancies [1]
We revealed that erastin can overcome docetaxel resistance and present as a magical molecule to augment docetaxel efficacy in ovarian cancer by inhibition of ABCB1
ABCB1-Overexpressing Ovarian Cancer Cells Are Resistant to Docetaxel and Erastin
Summary
Ovarian cancer threatens women’s health with high morbidity and mortality and is the leading cause of death in gynecological malignancies [1]. Multidrug resistance (MDR) in ovarian cancer is recognized as the primary cause of failing chemotherapeutic treatments and low survival rates in humans [5]. ABCB1 overexpression in cancers contributes to reduced intracellular chemotherapeutics accumulation and brings about resistance against a wide variety of the recently available antineoplastic agents like taxanes (docetaxel), vinca alkaloids (vinblastine), and anthracyclines (doxorubicin) [8,9,10,11]. Upregulated ABCB1 has been confirmed as the primary protein resulting in MDR in ovarian cancer treated with paclitaxel and related taxane drugs [12,13,14,15]. Drugs under tests that are aimed at ABCB1 to reserve MDR are far from satisfactory for clinical use
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