A Promising Microtubule Inhibitor Deoxypodophyllotoxin Exhibits Better Efficacy to Multi-Drug Resistant Breast Cancer than Paclitaxel via Avoiding Efflux Transport

Multi-drug resistance (MDR) is a common limitation for the clinical use of microtubule-targeting chemotherapeutic agents and it is the main factor for poor prognoses in cancer therapy. Here, we report on deoxypodophyllotoxin (DPT), a promising microtubule inhibitor in phase I, as a promising candidate to circumvent the obstacle. DPT remarkably suppressed the tumor growth in xenograft mice bearing either Paclitaxel (PTX)-sensitive MCF-7/S or acquired resistance MCF-7/Adr (MCF-7/A) cells. Also, DPT exhibited a similar accumulation in both tumors, while PTX displayed much a lower accumulation in the resistant tumors. In vitro, DPT exhibited a much lower resistance index (0.552) than those of PTX (754.5) or Etoposide (38.94) in both MCF-7/S and MCF-7/A cells. Flow cytometry analysis revealed that DPT (5, and 10 nM) caused the arrest of the G2/M phase in the two cell lines, while PTX (up to 10 nM) had no effect on the cell cycle progression of the MCF-7/A cells. Microtubule dynamics assays revealed that DPT destabilized microtubule assembly in a different mode. Cellular pharmacokinetic assays indicated comparable intracellular and subcellular accumulations of DPT in the two cell lines but a much lower retention of PTX in the MCF-7/A cells. Additionally, transport assays revealed that DPT was not the substrate of P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP), or Multi-drug Resistance-associated Protein 2 (MRP2), indicating a lower occurrence rate of multi-drug resistance. DPT might be a promising microtubule inhibitor for breast cancer therapy, especially for treatment of drug-resistant tumors.