Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model

  • Authors:
    • Amr S. Abu Lila
    • Chihiro Kato
    • Masakazu Fukushima
    • Cheng-Long Huang
    • Hiromi Wada
    • Tatsuhiro Ishida
  • View Affiliations

  • Published online on: February 1, 2016     https://doi.org/10.3892/ijo.2016.3367
  • Pages: 1399-1407
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Abstract

Malignant pleural mesothelioma (MPM) is an incurable cancer with an increasing incidence. Currently, pemetrexed (PMX)-based chemotherapy is the mainstay of chemotherapy for MPM, however, the outcome of PMX-based chemotherapy in patients with MPM is dismal. RNA interference (RNAi) technology has been considered as an effective tool to substantially enhance the therapeutic efficacy of chemotherapeutic agents in many preclinical and clinical settings. In this study, therefore, we investigated whether non-viral anti-thymidylate synthase RNAi embedded liposome (TS shRNA lipoplex) would effectively guide the downregulation of TS in human malignant mesothelioma MSTO-211H cells. Consequently, it enhanced the antitumor effect of PMX both in vitro and in vivo. TS shRNA effectively enhanced the in vitro cell growth inhibition upon treatment with PMX via downregulating TS expression in the MSTO-211H cell line. In in vivo orthotopic tumor model, the combined treatment of PMX and TS shRNA lipoplex efficiently combated the progression of orthotopic thoracic tumors and as a result prolonged mouse survival, compared to each single treatment. Our findings emphasize the pivotal relevance of RNAi as an effective tool for increasing the therapeutic efficacy of PMX, a cornerstone in the treatment regimens of MPM, and thereby, raising the possibility for the development of a novel therapeutic strategy, combination therapy of TS-shRNA and PMX, that can surpass many of the currently applied, but less effective, therapeutic regimens against lethal MPM.

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April 2016
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Copy and paste a formatted citation
APA
Abu Lila, A.S., Kato, C., Fukushima, M., Huang, C., Wada, H., & Ishida, T. (2016). Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model. International Journal of Oncology, 48, 1399-1407. https://doi.org/10.3892/ijo.2016.3367
MLA
Abu Lila, A. S., Kato, C., Fukushima, M., Huang, C., Wada, H., Ishida, T."Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model". International Journal of Oncology 48.4 (2016): 1399-1407.
Chicago
Abu Lila, A. S., Kato, C., Fukushima, M., Huang, C., Wada, H., Ishida, T."Downregulation of thymidylate synthase by RNAi molecules enhances the antitumor effect of pemetrexed in an orthotopic malignant mesothelioma xenograft mouse model". International Journal of Oncology 48, no. 4 (2016): 1399-1407. https://doi.org/10.3892/ijo.2016.3367