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

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

doi:10.1038/s41598-018-21642-0

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.

Highlights

Microtubules are highly dynamic structures that form spindle fibres during mitosis and are one of the most validated cancer targets
Disruption of microtubule dynamics results in failure of cells to complete mitosis, which leads to apoptotic cell death[5,6]
We have identified and characterized one of these compounds, SSE15206 [3-phenyl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide], as a microtubule polymerization inhibitor that overcomes multidrug resistance

Summary

Introduction

Microtubules are highly dynamic structures that form spindle fibres during mitosis and are one of the most validated cancer targets. We describe the discovery and characterization of SSE15206, a pyrazolinethioamide derivative [3-phenyl-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1Hpyrazole-1-carbothioamide] that has potent antiproliferative activities in cancer cell lines of different origins and overcomes resistance to microtubule-targeting agents. Microtubule-targeting agents (MTAs) constitute a large group of chemically diverse compounds that can be divided into two classes based on their ability to affect microtubule polymerization The stabilizing agents such as taxanes increase microtubule polymerization while destabilizing agents such as vinca alkaloids decrease it[7]. We demonstrate its effects on cell proliferation, cell cycle regulation, tubulin polymerization and apoptosis To our knowledge, this is the first study of the inhibition of tubulin polymerization by these compounds that incorporates their potential to overcome multidrug resistance

Methods

Results

Conclusion