Research Papers:

Structural recognition of tubulysin B derivatives by multidrug resistance efflux transporters in human cancer cells

Michal Stark and Yehuda G. Assaraf _

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Oncotarget. 2017; 8:49973-49987. https://doi.org/10.18632/oncotarget.18385

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Michal Stark1 and Yehuda G. Assaraf1

1The Fred Wyszkowski Cancer Research Laboratory, Department of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel

Correspondence to:

Yehuda G. Assaraf, email: [email protected]

Keywords: cancer, anti-microtubule agents, tubulysins, multidrug resistance, efflux transporters

Received: April 19, 2017    Accepted: May 07, 2017    Published: June 06, 2017


Multidrug resistance (MDR) is a major hindrance to curative chemotherapy of various human malignancies. Hence, novel chemotherapeutics must be evaluated for their recognition by MDR efflux transporters. Herein we explored the cytotoxic activity of synthetic tubulysin B (Tub-B, EC1009) derivatives (Tub-B-hydrazide/EC0347 and Tub-B bis-ether/EC1820), and their recognition by the MDR efflux transporters P-glycoprotein 1 (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP). Originally isolated from Myxobacteria, tubulysins exhibited potent cytotoxic activity via microtubule depolymerization, and evaded recognition by these MDR efflux pumps. We show that subtle modifications in the natural Tub-B structure enhance its cytotoxicity and drug efflux efficiency. Whereas increasing the lipophilicity of Tub-B drugs enhanced their diffusion into the cell and consequently decreased the IC50 values (≥ 0.27 nM), increasing drug polarity enhanced their recognition by P-gp (>200-fold resistance in P-gp-overexpressing cells). Furthermore, restricting drug exposure time to the clinically relevant 4 h pulse, markedly enhanced efflux by P-gp, resulting in a 1000-fold increased resistance, which was further enhanced upon increased P-gp levels (i.e. an additional 3-fold increase in P-gp levels resulted in >6,000-fold resistance). The unique ability of EC1009 to evade recognition by MDR efflux pumps warrants drug development of tubulysin B derivatives as potent antitumor agents which overcome MDR in cancer.

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