Summary
Combination chemotherapy has been shown to be more effective than single-agent therapy for many types of cancer, but both are known to induce drug resistance in cancer cells. Two major culprits in the development of this drug resistance are nuclear factor-κB (NF-κB) and the multidrug resistance (MDR) gene. For this reason, chemogene therapy is emerging as a viable alternative to conventional chemotherapy combinations. We have shown that transduction of the E2F-1 gene in melanoma cells markedly increases cell sensitivity to doxorubicin, thereby producing a synergistic effect on melanoma cell apoptosis. Our microarray results show that the NF-κB pathway and related genes undergo significant changes after the combined treatment of E2F-1 and doxorubicin. In fact, inactivation of NF-κB is associated with melanoma cell apoptosis induced by E2F-1 and doxorubicin, providing a link between the NF-κB signaling pathway and the chemosensitivity of melanoma cells after this treatment.
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Verweij, J. and de Jonge, M.J. (2000) Achievements and future of chemotherapy. Eur. J. Cancer 36, 1479–1487.
Liem, A.A., Chamberlain, M.P., Wolf. C.R., and Thompson, A.M. (2002) The role of signal transduction in cancer treatment and drug resistance. Eur. J. Surg. Oncol. 28, 679–684.
Meng, R.D., Phillips, P., and El-Deiry, W.S. (1999) p53-independent increase in E2F-1 expression enhances the cytotoxic effects of etoposide and of adriamycin. Int. J. Oncol. 14, 5–14.
Cheon, J., Ko, S.C., Gardner, T.A., Shirakawa, T., Gotoh, A., Kao, C., and Chung L.W. (1997) Chemogene therapy: osteocalcin promoter-based suicide gene therapy in combination with methotrexate in a murine osteosarcoma model. Cancer Gene. Ther. 4, 359–365.
Nemunaitis, J., Swisher, S.G., Timmons, T., Connors, D., Mack, M., Doerksen, L., Weill, D., Wait, J., Lawrence, D.D., Kemp, B.L., Fossella, F., Glisson, B.S., Hong, W.K., Khuri, F.R., Kurie, J.M., Lee, J.J. Lee, J.S., Nguyen, D.M., Nesbitt, J.C., Perez-Soler, R., Pisters, K.M.W., Putnam, J.B., Richli, W.R., Shin, D.M., Walsh, G.L., Merritt, J., and Roth, J. (2000) Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer. J. Clin. Oncol. 18, 609–622.
Yeh, P.Y., Chuang, S.E., Yeh, K.H., Song, Y.C., Ea, C.K., and Cheng, A.L. (2002) Increase of the resistance of human cervical carcinoma cells to cisplatin by inhibition of the MEK to ERK signaling pathway partly via enhancement of anticancer drug-induced NF-κB activation. Biochem. Pharmacol. 63, 1423–1430.
Yeh, P.Y., Chuang, S.E., Yeh, K.H., Song, Y.C., and Cheng, A.L. (2003) Involvement of nuclear transcription factor-κB in lowdose doxorubicin-induced drug resistance of cervical carcinoma cells. Biochem. Pharmacol. 66, 25–33.
Karin, M. (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441(7092), 431–436.
Ghosh, S. and Karin, M. (2002) Missing pieces in the NF-κB puzzle. Cell, 109(Suppl.), S81–S96.
Rothwarf, D.M. and Karin, M. (1999) The NF-κB activation pathway: a paradigm in information transfer from membrane to nucleus. Sci. STKE (October 26) 1999(5), RE1.
Karin, M. and Ben-Neriah, Y. (2000) Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18, 621–663.
Werner, S.L., Barken, D. and Hoffmann, A. (2005) Stimulus specificity of gene expression programs determined by temporal control of IKK activity. Science. 309, 1857–1861.
Park, J.M., Greten, F.R., Wong, A., Westrick, R.J., Arthur, S.C., Otsu, K., Hoffmann, A., Montminy, M. and Karin, M. (2005) Signaling pathways and genes that inhibit pathogen-induced macrophage apoptosis: CREB and NF-κB as key regulators. Immunity 23, 319–329.
Covert, M.W., Leung, T.H., Gaston, J.E. and Baltimore, D. (2005) Achieving stability of lipopolysaccharide-induced NF-κB activation. Science 309, 1854–1857.
Aggarwal, B.B. (2004) Nuclear factor-κB: the enemy within. Cancer Cell 6, 203–208.
Hao, H., Dong, Y.B., Bowling, M.T., Zhou, H.S. and McMasters, K.M. (2006) Alteration of gene expression in melanoma cells following combined treatment with E2F-1 and adriamycin. Anticancer Res. 26(3A), 1947–1956.
Acknowledgments
We are grateful to Mrs. Margaret Abby for her expert manuscript editing. Supported by NIH Grant R01CA90784 to KMM.
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Hao, H., Zhou, H.S., McMasters, K.M. (2009). Chemosensitization of Tumor Cells: Inactivation of Nuclear Factor-Kappa B Associated with Chemosensitivity in Melanoma Cells After Combination Treatment with E2F-1 and Doxorubicin. In: Walther, W., Stein, U. (eds) Gene Therapy of Cancer. Methods in Molecular Biology™, vol 542. Humana Press. https://doi.org/10.1007/978-1-59745-561-9_16
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DOI: https://doi.org/10.1007/978-1-59745-561-9_16
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