Identification and characterization of SSE15206, a microtubule depolymerizing agent that overcomes multidrug resistance

Safia Manzoor, Aishah Bilal, Sardraz Khan, Rahim Ullah, Sunniya Iftikhar, Abdul-Hamid M. Emwas, Meshari Alazmi, Xin Gao, Ali Jawaid, Rahman Shah Zaib Saleem, Amir Faisal

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Microtubules are highly dynamic structures that form spindle fibres during mitosis and are one of the most validated cancer targets. The success of drugs targeting microtubules, however, is often limited by the development of multidrug resistance. Here we describe the discovery and characterization of SSE15206, a pyrazolinethioamide derivative [3-phenyl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide] that has potent antiproliferative activities in cancer cell lines of different origins and overcomes resistance to microtubule-targeting agents. Treatment of cells with SSE15206 causes aberrant mitosis resulting in G2/M arrest due to incomplete spindle formation, a phenotype often associated with drugs that interfere with microtubule dynamics. SSE15206 inhibits microtubule polymerization both in biochemical and cellular assays by binding to colchicine site in tubulin as shown by docking and competition studies. Prolonged treatment of cells with the compound results in apoptotic cell death [increased Poly (ADP-ribose) polymerase cleavage and Annexin V/PI staining] accompanied by p53 induction. More importantly, we demonstrate that SSE15206 is able to overcome resistance to chemotherapeutic drugs in different cancer cell lines including multidrug-resistant KB-V1 and A2780-Pac-Res cell lines overexpressing MDR-1, making it a promising hit for the lead optimization studies to target multidrug resistance.
Original languageEnglish (US)
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Feb 19 2018

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