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Updated: Oct 2, 2026
Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
Published on: September 8, 2017
MS-209, a quinoline-type reversal agent, potentiates antitumor efficacy of docetaxel in multidrug-resistant solid
Mikihiko Naito1, Yasuhiro Matsuba, Shigeo Sato
1Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032.
Abstract:
The existence of multidrug-resistant (MDR) cells in cancer is a major obstacle to effective cancer chemotherapy. Expression of P-glycoprotein (P-gp) in cancer cells causes resistance against paclitaxel and docetaxel, as well as against vincristine and doxorubicin (ADM). MS-209 is a novel MDR-reversal agent currently under clinical evaluation, which is shown to be active against ADM and vincristine resistance in MDR cancer cells in vitro and in vivo. In this paper, we report the combined effect of MS-209 with docetaxel in various MDR cancer cell lines that express P-gp. MS-209 at 3 microM effectively overcame docetaxel resistance in MDR cancer cells, and this concentration was achieved in blood plasma for > 7 h without serious toxicity. To study the effect of MS-209 in a clinically relevant model, we compared the antitumor efficacy of docetaxel alone with that of docetaxel combined with MS-209 at equitoxic doses in established solid tumor xenograft models. Treatment with docetaxel alone at the maximal tolerated dose (MTD) showed an apparent antitumor activity to an intrinsically resistant HCT-15 tumor xenograft, and MS-209 additionally potentiated the antitumor activity of docetaxel. Against a MCF-7/ADM tumor xenograft expressing larger amounts of P-gp, docetaxel alone at the MTD showed no antitumor activity, whereas the MTD of docetaxel combined with MS-209 greatly reduced MCF-7/ADM tumor growth. These results indicate that MS-209 could be a clinically useful drug to modulate MDR in docetaxel therapy.
Insights
The novel agent MS-209 reverses multidrug resistance (MDR) in cancer cells. Combining MS-209 with docetaxel enhances its antitumor efficacy in MDR cancer models, suggesting clinical utility.
Area of Science:
- Oncology
- Pharmacology
- Cancer Chemotherapy
Background:
- Multidrug resistance (MDR) in cancer cells, often mediated by P-glycoprotein (P-gp), significantly limits the effectiveness of chemotherapy.
- P-gp expression confers resistance to crucial chemotherapeutic agents like paclitaxel, docetaxel, vincristine, and doxorubicin (ADM).
- MS-209 is an investigational MDR-reversal agent demonstrating activity against ADM and vincristine resistance.
Purpose of the Study:
- To evaluate the combined effect of MS-209 and docetaxel in P-gp-expressing MDR cancer cell lines.
- To assess the in vivo antitumor efficacy of docetaxel combined with MS-209 in solid tumor xenograft models.
Main Methods:
- In vitro assessment of MS-209's ability to overcome docetaxel resistance in MDR cancer cell lines.
- Pharmacokinetic analysis of MS-209 to determine plasma concentration and duration.
- In vivo studies comparing docetaxel alone versus docetaxel plus MS-209 at equitoxic doses in HCT-15 and MCF-7/ADM tumor xenografts.
Main Results:
- MS-209 (3 microM) effectively reversed docetaxel resistance in MDR cancer cells, achieving sustained plasma levels without significant toxicity.
- In docetaxel-resistant HCT-15 xenografts, MS-209 potentiated the antitumor activity of docetaxel.
- In MCF-7/ADM xenografts with high P-gp expression, docetaxel alone was ineffective, but combination therapy with MS-209 significantly inhibited tumor growth.
Conclusions:
- MS-209 demonstrates significant potential as an MDR-reversal agent in combination with docetaxel.
- The combination therapy shows enhanced antitumor efficacy in preclinical models of docetaxel-resistant and P-gp-expressing cancers.
- MS-209 may represent a valuable therapeutic strategy to overcome MDR in clinical docetaxel treatment.
