A Novel Nitrobenzoate Microtubule Inhibitor that Overcomes Multidrug Resistance Exhibits Antitumor Activity

Abstract

Multidrug resistance is a major limitation for microtubule-binding agents in cancer treatment. Here we report a novel microtubule inhibitor (2-morpholin-4-yl-5-nitro-benzoic acid 4-methylsulfanyl-benzyl ester, IMB5046), its cytotoxicity against multidrug-resistant cell lines and its antitumor efficacy in animal models. IMB5046 disrupted microtubule structures in cells and inhibited purified tubulin polymerization in vitro. It bound to the colchicine pocket of tubulin. IMB5046 displayed potent cytotoxicity against multiple tumor cell lines with an IC50 range of 0.037–0.426 μM. Notably, several multidrug-resistant cell lines which were resistant to colchicine, vincristine and paclitaxel remained sensitive to IMB5046. IMB5046 was not a P-glycoprotein substrate. IMB5046 blocked cell cycle at G2/M phase and induced cell apoptosis. Microarray assay indicated that the differentially expressed genes after IMB5046 treatment were highly related to immune system, cell death and cancer. In a mouse xenograft model IMB5046 inhibited the growth of human lung tumor xenograft by 83% at a well-tolerated dose. It is concluded that IMB5046 is a tubulin polymerization inhibitor with novel chemical structure and can overcome multidrug resistance. It is a promising lead compound for cancer chemotherapy, especially for treatment of multidrug-resistant tumors.

Super-Resolution Microscopy Reveals That Stromal Interaction Molecule 1 Trafficking Depends on Microtubule Dynamics

“…First, since the expression level of STIM1 and EB1 in different types of cells could be variable (Roos et al, 2005;DeHaven et al, 2007), the different cell lines applied in those studies might lead to distinct results. Moreover, the treatment duration of taxol in Grigoriev's study last for only 2 h, and which is much shorter than the 24 h in other study (Dowdy et al, 2006;Zheng et al, 2016). Insufficient treatment might influence the effect of microtubule stabilization.…”

Cytoskeletal Proteins in Cancer and Intracellular Stress: A Therapeutic Perspective

“…The identification of novel inhibitors, such as IMB5046, with anti-tumour effects in cell lines resistant to existing microtubule inhibitors (such as vincristine and paclitaxel), as well as the discovery of epothilones, provide alternative options of microtubule-specific drugs with better efficacy and lower toxicity. Nevertheless, the current solution to overcoming chemoresistance remains a race between developing new analogues and tumour cells acquiring resistance [5,98,99].…”

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

“…Compound 76, in contrast to colchicine and other MTAs, overcame drug resistance in P-gp overexpressing KBv200 cells. Thus, 76 could act as a promising lead and novel scaffold targeting the CBS in a divergent manner when compared to other CBSIs discussed in this review [142,143]. Despite striking deviations from colchicine's structure, 77 is a competitive inhibitor of colchicine at the CBS.…”