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Molecular changes to HeLa cells on continuous exposure to cisplatin or paclitaxel

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Abstract

Objective: To achieve a reversal of multidrug resistance (MDR) in cancer chemotherapy, it is crucial to clarify the characteristics of MDR cells generated by various types of chemotherapeutic agents and to find novel targets. Methods: Cisplatin- and paclitaxel-resistant HeLa sublines (HeLa/CDDP and HeLa/TXL, respectively) were established by continuous exposure and their cellular changes were examined based on growth inhibition assays, the transport activity of P-glycoprotein/MDR1, and a RT-PCR analysis of MDR-related factors. Results: HeLa/CDDP cells showed cross-resistance to platinum derivatives, whereas HeLa/TXL cells were resistant to a variety of MDR1 substrates. Transport activity of MDR1 was reduced in HeLa/CDDP cells and the expression of MDR1 was significantly accelerated in HeLa/TXL cells, compared with HeLa cells. In addition, the expression levels of MDR-related transporters (MRP1–5 or BCRP), βtubulin which is a target for taxanes, and apoptosis-regulated factors were comparable among the three cell lines. On the other hand, the mRNA levels of γ-glutamyl transferase, but not γ-glutamyl cysteine synthetase, were higher in HeLa/CDDP cells than in HeLa and HeLa/TXL cells. Conclusions: HeLa/CDDP cells showed decreased activity and expression of MDR1 and overexpression of \( \ifmmode\expandafter\tilde\else\expandafter\sim \fi{\gamma }{\text{-GT}} \) but not \( \ifmmode\expandafter\tilde\else\expandafter\sim \fi{\gamma }{\text{-GCS,}} \) whereas the activity of MDR1 in HeLa/TXL cells was significantly enhanced. Thus, the molecular changes to HeLa cells caused by continuous exposure to cisplatin or paclitaxel were in part clarified, and therefore an understanding of the cellular changes induced by chemotherapeutic agents will be necessary to establish a strategy for reversing MDR.

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Acknowledgements

This work was supported in part by an “Academic Frontier” Project for a Matching Fund Subsidy for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Hospital Pharmacy, Faculty of Pharmaceutical Sciences, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, 607-8414, Kyoto, Japan

    Kohji Takara, Yukihisa Obata, Eri Yoshikawa, Noriaki Kitada, Noriaki Ohnishi & Teruyoshi Yokoyama

  2. Department of Hospital Pharmacy, School of Medicine, Kobe University, 7-5-2 Kusunoki-cho, Chuo-ku, 650-0017, Kobe, Japan

    Toshiyuki Sakaeda

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  1. Kohji Takara
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Correspondence to Kohji Takara.

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Takara, K., Obata, Y., Yoshikawa, E. et al. Molecular changes to HeLa cells on continuous exposure to cisplatin or paclitaxel. Cancer Chemother Pharmacol 58, 785–793 (2006). https://doi.org/10.1007/s00280-006-0226-5

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  • DOI: https://doi.org/10.1007/s00280-006-0226-5

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