A Novel Microtubule Inhibitor Overcomes Multidrug Resistance in Tumors

Abstract

Microtubule inhibitors as chemotherapeutic drugs are widely used for cancer treatment. However, the development of multidrug resistance (MDR) in cancer is a major challenge for microtubule inhibitors in their clinical implementation. From a high-throughput drug screen using cells transformed by oncogenic RAS, we identify a lead heteroaryl amide compound that blocks cell proliferation. Analysis of the structure-activity relationship indicated that this series of scaffolds (exemplified by MP-HJ-1b) represents a potent inhibitor of tumor cell growth. MP-HJ-1b showed activities against a panel of more than 1,000 human cancer cell lines with a wide variety of tissue origins. This compound depolymerized microtubules and affected spindle formation. It also induced the spike-like conformation of microtubules and, which is different from typical microtubule modulators. Structural analysis revealed that this series of compounds bound the colchicine pocket at the intra-dimer interface, although mostly not overlapping with colchicine binding. MP-HJ-1b displayed favorable pharmacological properties for overcoming tumor MDR, both and Taken together, our data reveal a novel scaffold represented by MP-HJ-1b that can be developed as a cancer therapeutic against tumors with MDR. Paclitaxel is a widely used chemotherapeutic drug in patients with multiple types of cancer. However, resistance to paclitaxel is a challenge. This study describes a novel class of microtubule inhibitors with the ability to circumvent multidrug resistance across multiple tumor cell lines. .

Mitochondrial TXNRD3 confers drug resistance via redox-mediated mechanism and is a potential therapeutic target in vivo

“…Development of drug resistance in tumor cells is a major challenge in clinical treatment of cancer [ 1 ]. This is particularly true in case of tyrosine kinases inhibitors used in targeted therapy, where mutations of the target genes and altered expression of the molecules involved in the relevant pathways often occur after a period of drug treatment [ 2 , 3 ].…”

Esomeprazole overcomes paclitaxel‐resistance and enhances anticancer effects of paclitaxel by inducing autophagy in A549/Taxol cells

“…In fact, the drug‐resistance in NSCLC often accounts for more malignancy, reflecting as the rapid proliferation, invasiveness, and migration of cancer cells and the poor efficacy of anticancer drugs (F. Q. Chen et al, 2017; Crystal et al, 2014; Ning et al, 2018). In this study, we constructed a paclitaxel‐resistant A549 cell line through the stepwise selection method and renamed it as A549/Taxol cells, which exhibited a significantly stronger proliferate ability and cell division rate compared with its parental A549 cells under the same culture conditions.…”

PTPN2 regulates the activation of KRAS and plays a critical role in proliferation and survival of KRAS-driven cancer cells

“…Cell viability assays were carried out using the CellTiter-Glo® Luminescent Cell Viability Assay as previously described ( 48 ). H460, PaTu8988T, HCT-116, A549, DLD-1, HT-1080, and SK-MEL-30 cells were transfected with siRNA via reverse transfection using Dharmafect 1 or RNAiMAX at a final concentration of 50 n m and seeded in regular 96-well–plates at a density of 5 × 10 3 to 1 × 10 4 cells/well.…”