Abstract
Multidrug 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 1, as a promising candidate to circumvent this obstacle. DPT remarkably suppressed 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 similar accumulation in both tumors, whereas 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 arrest of the G2/M phase in the two cell lines, whereas PTX (up to 10 nM) had no effect on 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, breast cancer resistance protein, or MDR-associated protein 2, indicating a lower occurrence rate of MDR. DPT might be a promising microtubule inhibitor for breast cancer therapy, especially for treatment of drug-resistant tumors.
Footnotes
- Received November 10, 2017.
- Accepted February 22, 2018.
↵1 X.Z. and G.W. contributed equally to this work.
The work was supported by the China National Nature Science Foundation [Grants 81573496 and 81530098], Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics Projects [Grant BM2012012], Jiangsu Province Nature Science Foundation [Grant BK20160076], China “Creation of New Drugs” Key Technology Projects [Grant 2015ZX09501001], the Foundation for Innovative Research Groups of the National Natural Science Foundation of China [Grant 81421005], and the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University [Grant SKLNMZZCX201608].
↵This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics
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