Hernandezine, a Bisbenzylisoquinoline Alkaloid with Selective Inhibitory Activity against Multidrug-Resistance-Linked ATP-Binding Cassette Drug Transporter ABCB1.

The overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 (P-glycoprotein, MDR1) is the most studied mechanism of multidrug resistance (MDR), which remains a major obstacle in clinical cancer chemotherapy. Consequently, resensitizing MDR cancer cells by inhibiting the efflux function of ABCB1 has been considered as a potential strategy to overcome ABCB1-mediated MDR in cancer patients. However, the task of developing a suitable modulator of ABCB1 has been hindered mostly by the lack of selectivity and high intrinsic toxicity of candidate compounds. Considering the wide range of diversity and relatively nontoxic nature of natural products, developing a potential modulator of ABCB1 from natural sources is particularly valuable. Through screening of a large collection of purified bioactive natural products, hernandezine was identified as a potent and selective reversing agent for ABCB1-mediated MDR in cancer cells. Experimental data demonstrated that the bisbenzylisoquinoline alkaloid hernandezine is selective for ABCB1, effectively inhibits the transport function of ABCB1, and enhances drug-induced apoptosis in cancer cells. More importantly, hernandezine significantly resensitizes ABCB1-overexpressing cancer cells to multiple chemotherapeutic drugs at nontoxic, nanomolar concentrations. Collectively, these findings reveal that hernandezine has great potential to be further developed into a novel reversal agent for combination therapy in MDR cancer patients.

Overexpression of human ABCB1 in cancer cells leads to reduced activity of GSK461364, a specific inhibitor of polo-like kinase 1.

Polo-like kinase 1 (Plk1) is a serine/threonine kinase involved in the regulation of mitosis and is overexpressed in many tumor types. Inhibition of Plk1 leads to cell cycle arrest, onset of apoptosis, and cell death, thus Plk1 has emerged as an important target for cancer treatment. GSK461364 is a potent inhibitor of Plk1 that inhibits the proliferation of multiple human cancer cell lines by promoting G2/M cell cycle arrest at low concentrations. However, as is the case for many therapeutic drugs, the risk of developing drug resistance to GSK461364 can present a therapeutic challenge to clinicians. Since the overexpression of ATP-binding cassette (ABC) drug transporter ABCB1 is one of the most common mechanisms of drug resistance, we aimed to investigate the effect of ABCB1 on the cellular efficacy of GSK461364. In this study, we observed a significantly reduced activity of GSK461364 in cells overexpressing human ABCB1. We showed that GSK461364 stimulates the ABCB1 ATPase activity and competitively inhibits ABCB1-mediated efflux of calcein-AM in a concentration-dependent manner. Moreover, as a way to assess the impact of ABCB1 on the efficacy of GSK461364, we evaluated the G2/M cell cycle arrest and apoptosis induced by GSK461364. We discovered that, by inhibiting the function of ABCB1, the reduced G2/M cell cycle arrest, apoptosis, and sensitivity to GSK461364 treatment in ABCB1-overexpressing cells can be significantly restored. In conclusion, in order to achieve a better therapeutic outcome, combination therapy of GSK461364 with a modulator of ABCB1 should be further investigated as a potential treatment approach.

Human ABCB1 (P-glycoprotein) and ABCG2 mediate resistance to BI 2536, a potent and selective inhibitor of Polo-like kinase 1.

The overexpression of the serine/threonine specific Polo-like kinase 1 (Plk1) has been detected in various types of cancer, and thus has fast become an attractive therapeutic target for cancer therapy. BI 2536 is the first selective inhibitor of Plk1 that inhibits cancer cell proliferation by promoting G2/M cell cycle arrest at nanomolar concentrations. Unfortunately, alike most chemotherapeutic agents, the development of acquired resistance to BI 2536 is prone to present a significant therapeutic challenge. One of the most common mechanisms for acquired resistance in cancer chemotherapy is associated with the overexpression of ATP-binding cassette (ABC) transporters ABCB1, ABCC1 and ABCG2. Here, we discovered that overexpressing of either ABCB1 or ABCG2 is a novel mechanism of acquired resistance to BI 2536 in human cancer cells. Moreover, BI 2536 stimulates the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner, and inhibits the drug substrate transport mediated by these transporters. More significantly, the reduced chemosensitivity and BI 2536-mediated G2/M cell cycle arrest in cancer cells overexpressing either ABCB1 or ABCG2 can be significantly restored in the presence of selective inhibitor or other chemotherapeutic agents that also interact with ABCB1 and ABCG2, such as tyrosine kinase inhibitors nilotinib and lapatinib. Taken together, our findings indicate that in order to circumvent ABCB1 or ABCG2-mediated acquired resistance to BI 2536, a combined regimen of BI 2536 and inhibitors or clinically active drugs that potently inhibit the function of ABC drug transporters, should be considered as a potential treatment strategy in the clinic.