Javier Yu Peng Koh, Yoko Itahana, Alexander Krah, Habib Mostafa, Mingmin Ong, Sahana Iwamura, Dona Mariya Vincent, Sabhashina Radha Krishnan, Weiying Ye, Pierre Wing Chi Yim, Tushar M. Khopade, Kunihiko Chen, Pui San Kong, Lin-Fa Wang, Roderick W. Bates, Yasuhisa Kimura, Rajesh Viswanathan, Peter J. Bond, Koji Itahana
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引用次数: 0
Abstract
Chemotherapy-induced drug resistance remains a major cause of cancer recurrence and patient mortality. ATP binding cassette subfamily B member 1 (ABCB1) transporter overexpression in tumors contributes to resistance, yet current ABCB1 inhibitors have been unsuccessful in clinical trials. To address this challenge, we propose a new strategy using tryptophan as a lead molecule for developing ABCB1 inhibitors. Our idea stems from our studies on bat cells, as bats have low cancer incidences and high ABCB1 expression. We hypothesized that potential ABCB1 substrates in bats could act as competitive inhibitors in humans. By molecular simulations of ABCB1-substrate interactions, we generated a benzylated Cyclo-tryptophan (C3N-Dbn-Trp2) that inhibits ABCB1 activity with efficacy comparable to or better than the classical inhibitor, verapamil. C3N-Dbn-Trp2 restored chemotherapy sensitivity in drug-resistant human cancer cells with no adverse effect on cell proliferation. Our unique approach presents a promising lead toward developing effective ABCB1 inhibitors to treat drug-resistant cancers. ATP-binding cassette transporter ABCB1 is known to be involved in drug resistance in cancer treatment, however, current ABCB1 inhibitors have not been successful in clinical trials due to their potential cytotoxicity. Here, the authors hypothesize that potential ABCB1 substrates in bats could act as competitive inhibitors against ABCB1 in humans, and identify the tryptophan structure as a promising lead structure for the development of non-toxic ABCB1 inhibitors.
期刊介绍:
Communications Chemistry is an open access journal from Nature Research publishing high-quality research, reviews and commentary in all areas of the chemical sciences. Research papers published by the journal represent significant advances bringing new chemical insight to a specialized area of research. We also aim to provide a community forum for issues of importance to all chemists, regardless of sub-discipline.