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Enhancing effect of connexin 32 gene on vinorelbine-induced cytotoxicity in A549 lung adenocarcinoma cells

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Abstract

Purpose

Connexin (Cx) genes exert negative growth effects on tumor cells with certain cell specificity, and tumor-suppressive effects of the Cx genes contribute to enhancement of chemotherapeutical agents-induced cytotoxicity in some cancer cells. Since we and others have been reported that Cx32 acts as a tumor suppressor gene in lung adenocarcinomas, this study was undertaken to estimate if the combination of Cx32-dependent tumor-suppressive effect and vinorelbine (VBN), a chemotherapeutic agent which has been utilized for clinical lung adenocarcinoma treatment, could be effective in enhancing the sensitivity of the lung cancer to VBN treatment.

Methods

We established the A549 cells (a human lung adenocarcinoma cell line) which had stable expression of Cx32 and estimated effect of Cx32 on VBN-induced cytotoxicity in the established cells.

Results

Cx32 expression in A549 cells significantly potentiated VBN-induced cytotoxicity on the cells due to enhancement of apoptosis induction. The enhancing cytotoxicity in A549 cells by Cx32 mainly depended on a decrease in expression of multi-drug resistance-1 (MDR-1) gene responsible for reduction of VBN accumulation into the cells. We also observed that silencing of Cx32 by siRNA treatment elevated the expression level of MDR-1 mRNA in A549 cells and that inhibition of MDR-1 gene product-dependent function enhanced VBN-induced cytotoxicity in the cells.

Conclusion

These results suggest that Cx32 contributes to the enhancement of VBN-induced cytotoxicity in A549 cells via the reduction of MDR-1 expression.

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Acknowledgment

This study was supported by a research grant for Health Sciences Focusing on Drug Innovation from the Japan Health Sciences Foundation (KH21012).

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Authors and Affiliations

  1. Project for Complementary Factors, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8636, Japan

    Hiromi Sato, Keiko Fukumoto, Sachio Hada, Hiromi Hagiwara, Eriko Fujimoto & Tomohiro Yano

  2. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chiba, 260-8675, Japan

    Hiromi Sato, Eriko Fujimoto, Etsuko Negishi & Koichi Ueno

  3. Japan Health Sciences Foundation, 13-4 Nihonbashi-Kodenmacho, Chuo, Tokyo, 103-0001, Japan

    Hiromi Hagiwara

Authors
  1. Hiromi Sato
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  2. Keiko Fukumoto
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  3. Sachio Hada
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  8. Tomohiro Yano
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Correspondence to Tomohiro Yano.

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Sato, H., Fukumoto, K., Hada, S. et al. Enhancing effect of connexin 32 gene on vinorelbine-induced cytotoxicity in A549 lung adenocarcinoma cells. Cancer Chemother Pharmacol 60, 449–457 (2007). https://doi.org/10.1007/s00280-006-0406-3

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