BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe

Overcoming resistance to mitochondrial apoptosis by BZML‐induced mitotic catastrophe is enhanced by inhibition of autophagy in A549/Taxol cells

“…Further, BZML‐treated A549 and A549/Taxol cells in the presence or absence of NAC for 72 hours were detected by Annexin V‐FITC/PI staining and the MTT assay. However, the phosphatidylserine in outer cell membrane (Annexin V‐FITC positive) is a marker of apoptosis, and BZML‐induced MC also possesses this feature in A549/Taxol cells . Here, the BZML‐induced Annexin V‐FITC‐positive cells were clearly reduced by NAC in A549 cells, but not in A549/Taxol cells (Figure C).…”

“…A549 and A549/Taxol cells were grown in RPMI 1640 supplemented with 10% FBS at 37°C with 5% CO 2 in a humidified incubator. A549/Taxol cells were periodically cultured in 300 nM Taxol to maintain MDR and shifted into Taxol‐free medium for 1 week before used …”

“…Importantly, the different functional forms of autophagy depend on the genetic background of cells, the microenvironment and the type of drug . Recently, other types of PCD, including necroptosis, MC and senescence, have been reported . MC, a p53‐independent apoptosis‐like cell death mode to against apoptosis resistance, has received more attention .…”

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

“…Currently, ABI‐231, as VERU‐111, is under clinical trials in men with advanced castration resistant prostate cancer (NCT 03752099). The compounds exhibited similar potency to MDR cells compared with corresponding parent cells . They also demonstrated synergistic action through the combination of ABI‐274 and vemurafenib to overcome vemurafenib‐acquired resistance in BRAF (V600E) melanoma.…”

“…Mechanistic studies showed that BZML decreased P‐gp expression at the protein and mRNA levels. Cell morphology changes and the expression of apoptosis‐related proteins denoted that BZML‐induced mitotic catastrophe to A549/taxol‐resistant cells in a p53‐independent, apoptotic‐like pathway, whereas BZML‐caused apoptosis to A549 cells . Verubulin (MPC‐6827) ( 30 ) is a quinazoline derivative that showed potent antineoplastic activities against diverse tumors and promoted apoptosis in both sensitive and MDR cancer cell phenotypes .…”