This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Frese, S. Articles by Schmid, R. A. Search for Related Content PubMed PubMed Citation Articles by Frese, S. Articles by Schmid, R. A.

Cardiac Glycosides Initiate Apo2L/TRAIL-Induced Apoptosis in Non–Small Cell Lung Cancer Cells by Up-regulation of Death Receptors 4 and 5

¹ Division of General Thoracic Surgery, University Hospital Berne and ² The Tiefenau Laboratory, Department of Clinical Research, University of Berne, Switzerland

Requests for reprints: Steffen Frese, Laboratory of Thoracic Surgery, Department of Clinical Research, University Hospital Berne, Murtenstrasse 35, Room C807, CH-3010 Berne, Switzerland. Phone: 41-31-632-25-46; Fax: 41-31-632-04-54; E-mail: steffen.frese{at}email.de.

Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (Apo2L/TRAIL) belongs to the TNF family known to transduce their death signals via cell membrane receptors. Because it has been shown that Apo2L/TRAIL induces apoptosis in tumor cells without or little toxicity to normal cells, this cytokine became of special interest for cancer research. Unfortunately, cancer cells are often resistant to Apo2L/TRAIL-induced apoptosis; however, this can be at least partially negotiated by parallel treatment with other substances, such as chemotherapeutic agents. Here, we report that cardiac glycosides, which have been used for the treatment of cardiac failure for many years, sensitize lung cancer cells but not normal human peripheral blood mononuclear cells to Apo2L/TRAIL-induced apoptosis. Sensitization to Apo2L/TRAIL mediated by cardiac glycosides was accompanied by up-regulation of death receptors 4 (DR4) and 5 (DR5) on both RNA and protein levels. The use of small interfering RNA revealed that up-regulation of death receptors is essential for the demonstrated augmentation of apoptosis. Blocking of up-regulation of DR4 and DR5 alone significantly reduced cell death after combined treatment with cardiac glycosides and Apo2L/TRAIL. Combined silencing of DR4 and DR5 abrogated the ability of cardiac glycosides and Apo2L/TRAIL to induce apoptosis in an additive manner. To our knowledge, this is the first demonstration that glycosides up-regulate DR4 and DR5, thereby reverting the resistance of lung cancer cells to Apo2/TRAIL-induced apoptosis. Our data suggest that the combination of Apo2L/TRAIL and cardiac glycosides may be a new interesting anticancer treatment strategy. (Cancer Res 2006; 66(11): 5867-74)

This article has been cited by other articles:

				Z. Wang, M. Zheng, Z. Li, R. Li, L. Jia, X. Xiong, N. Southall, S. Wang, M. Xia, C. P. Austin, et al. Cardiac Glycosides Inhibit p53 Synthesis by a Mechanism Relieved by Src or MAPK Inhibition Cancer Res., August 15, 2009; 69(16): 6556 - 6564. [Abstract] [Full Text] [PDF]

				S. FRESE, A. SCHULLER, M. FRESE-SCHAPER, M. GUGGER, and R. A. SCHMID Cytotoxic Effects of Camptothecin and Cisplatin Combined with Tumor Necrosis Factor-related Apoptosis-inducing Ligand (Apo2L/TRAIL) in a Model of Primary Culture of Non-small Cell Lung Cancer Anticancer Res, August 1, 2009; 29(8): 2905 - 2911. [Abstract] [Full Text] [PDF]

				P. Yang, D. G. Menter, C. Cartwright, D. Chan, S. Dixon, M. Suraokar, G. Mendoza, N. Llansa, and R. A. Newman Oleandrin-mediated inhibition of human tumor cell proliferation: Importance of Na,K-ATPase {alpha} subunits as drug targets Mol. Cancer Ther., August 1, 2009; 8(8): 2319 - 2328. [Abstract] [Full Text] [PDF]

				C. D. Simpson, I. A. Mawji, K. Anyiwe, M. A. Williams, X. Wang, A. L. Venugopal, M. Gronda, R. Hurren, S. Cheng, S. Serra, et al. Inhibition of the Sodium Potassium Adenosine Triphosphatase Pump Sensitizes Cancer Cells to Anoikis and Prevents Distant Tumor Formation Cancer Res., April 1, 2009; 69(7): 2739 - 2747. [Abstract] [Full Text] [PDF]

				T. Yasuda, T. Yoshida, A. E. Goda, M. Horinaka, K. Yano, T. Shiraishi, M. Wakada, Y. Mizutani, T. Miki, and T. Sakai Anti-Gout Agent Allopurinol Exerts Cytotoxicity to Human Hormone-Refractory Prostate Cancer Cells in Combination with Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Mol. Cancer Res., December 1, 2008; 6(12): 1852 - 1860. [Abstract] [Full Text] [PDF]

				I. Prassas, M. Paliouras, A. Datti, and E. P. Diamandis High-Throughput Screening Identifies Cardiac Glycosides as Potent Inhibitors of Human Tissue Kallikrein Expression: Implications for Cancer Therapies Clin. Cancer Res., September 15, 2008; 14(18): 5778 - 5784. [Abstract] [Full Text] [PDF]

				R. A. Newman, Y. Kondo, T. Yokoyama, S. Dixon, C. Cartwright, D. Chan, M. Johansen, and Peiying Yang Autophagic Cell Death of Human Pancreatic Tumor Cells Mediated by Oleandrin, a Lipid-Soluble Cardiac Glycoside Integr Cancer Ther, December 1, 2007; 6(4): 354 - 364. [Abstract] [PDF]

				W. Chen, X. Wang, J. Zhuang, L. Zhang, and Y. Lin Induction of death receptor 5 and suppression of survivin contribute to sensitization of TRAIL-induced cytotoxicity by quercetin in non-small cell lung cancer cells Carcinogenesis, October 1, 2007; 28(10): 2114 - 2121. [Abstract] [Full Text] [PDF]