Strategies to Overcome Multi-Drug Resistance in Cancer
Date
2018
Authors
Muthiah, Divya
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Abstract
Multidrug resistance (MDR) is a common cause of chemotherapy treatment failure and can be a significant obstacle in cancer therapy. A key contributor to MDR is the overexpression of ABC transporters such as ABCB1 and ABCG2. Over the last 30 years researchers have identified three generations of inhibitors to overcome drug resistance caused by ABCB1 and ABCG2. Despite intensive efforts, a clinically usable inhibitor is yet to be identified. All three generations of inhibitors have failed due to poor cytotoxic potency, off target effects or adverse reactions. An alternative strategy to overcome MDR could be to use compounds that not only inhibit the transporter but also indirectly overcome resistance by down regulating expression of the relevant transporter through signal transduction pathways. This investigation aimed to overcome ABCB1- and ABCG2- mediated drug resistance and inhibit cancer cell proliferation using novel noscapine derivatives or the kinase inhibitor ZSTK474, in combination with existing anticancer agents such as vinblastine or mitoxantrone. It also aimed to elucidate the mechanism of action of these compounds and determine if these compounds directly or indirectly inhibited the function of ABCB1 and ABCG2. Noscapine and its derivatives were anti-proliferative in control wildtype cells (MCF7WT), and cancer cells overexpressing ABCB1 (NCI/ADRRES) or ABCG2 (MFC7FLV1000). The activity of compounds were also unaffected by the expression of ABCB1 and ABCG2. The combination of noscapine or selected noscapine derivatives with currently used anti-cancer agents potentiated anti-proliferative 11 effects in all three cell lines. Noscapine and it derivatives achieved potentiation by a) using inherent anti-cancer activity that is unaltered in the presence of ABCB1 and ABCG2 and b) increasing intracellular drug accumulation by directly inhibiting the efflux by the pump. ZSTK474 was anti-proliferative and its activity was unaffected by the ABCB1 and ABCG2 expression. The combination of ZSTK474 with anti-cancer agents in sensitive and resistant cells produced synergistic anti-proliferative effects. ZSTK474 achieved synergy by a) being unaffected by the resistance phenotype and inhibiting cancer cell proliferation, b) reducing ABCB1 and ABCG2 expression by inhibition of protein synthesis, and c) by increasing intracellular substrate accumulation via inhibition of efflux mediated by ABCB1 and ABCG2. In summary, ZSTK474 and selected noscapine derivatives overcame the resistance phenotype via multiple modes of action. The use of ZSTK474 or noscapine derivatives with anti-cancer agents used in the clinic could overcome ABCB1- or ABCG2-mediated MDR to reduce side effects for cancer patients and warrants further investigation.
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Cancer, Multi-Drug Resistance, ABC Transporters, ABCB1, ABCG2, Chemotherapy, Noscapine, ZSTK474
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Open Access
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