Oleandrin Activates Apoptosis and Inhibits Metastasis of A375 Human Melanoma Cells

Authors

  • Canan Eroğlu Güneş Department of Medical Biology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
  • Fatma Seçer Çelik Department of Medical Biology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
  • Mücahit Seçme Department of Medical Biology, Faculty of Medicine, Pamukkale University, Denizli, Turkey
  • Ercan Kurar Department of Medical Biology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey

Keywords:

Apoptosis, Invasion, Melanoma cells, Metastasis, Oleandrin

Abstract

Skin cancer has an increasing incidence worldwide. Non-melanoma skin cancers and malignant melanomas are the most common skin malignancy. Nerium oleander L., which is a member Apocynaceae family, has historically been used in the treatment of hemorrhoids, leprosy and snake bites. Oleandrin is one of the cardiac glycosides obtained from N. oleander. The study aimed to evaluate the anticancer effects of oleandrin in A375 human melanoma cells via apoptosis, metastasis and invasion pathways. The effect of oleandrin on cell viability was evaluated using an XTT cell viability assay. Expressions of 8 genes in apoptosis and 10 genes in metastasis and invasion were determined by RT-qPCR. The IC50 dose of oleandrin was found to be 47 nM for 48 h in A375 melanoma cells using CompuSyn version 1.0 software. Oleandrin treatment significantly increased the expression of CASP9, FAS, CYCS, CDH1 and TIMP3; however, significantly decreased the expression of BCL2, P53, CDH2 and TGFB3 in A375 cells. In conclusion, changes in expression levels of apoptosis, metastasis and invasion genes indicated that oleandrin has an apoptotic and anti-metastatic effect in A375 cells.

References

Afaq, F., Saleem, M., Aziz M. H., & Mukhtar, H. (2004). Inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion markers in CD-1 mouse skin by oleandrin. Toxicol. Appl. Pharmacol., 195(3), 361-369. https://doi.org/10.1016/j.taap.2003.09.027

American Cancer Society. (2016). Cancer Facts & Figures 2016. Atlanta: American Cancer Society, p.14.

American Cancer Society. (2020). Cancer Facts & Figures 2020. Atlanta: American Cancer Society, p.24.

Blok, L. J., Chang, G. T., Steenbeek-Slotboom, M., van Weerden, W. M., Swarts, H.G., De Pont, J. J., van Steenbrugge, G. J., & Brinkmann, A.O. (1999). Regulation of expression of Na+,K+-ATPase in androgen-dependent and androgen-independent prostate cancer. Br J Cancer., 81(1), 28–36. https://doi.org/10.1038/sj.bjc.6690647

Botelho, A. F. M., Pierezan, F., Soto-Blanco, B., & Mello, M. M. (2019). A review of cardiac glycosides: structure, toxicokinetics, clinical signs, diagnosis and antineoplastic potential. Toxicon., 158, 63-68. https://doi.org/10.1016/j.toxicon.2018.11.429

Carbik, I., Başer. K. H. C., Özel, H. Z., Ergun, B.,0 & Wagner, H. (1990). Immunologically active polysaccharides from the aqueous extract of Nerium oleander. Planta Med., 56, 668. https://doi.org/10.1055/s-2006-961333

Chen, J. Q., Contreras, R. G., Wang, R., Fernandez, S. V., Shoshani, L., Russo, I. H., Cereijido, M., & Russo, J. (2006). Sodium/potassium ATPase (Na+, K+-ATPase) and ouabain/related cardiac glycosides: A new paradigm for development of anti- breast cancer drugs?. Breast Cancer Res Treat., 96(1), 1–15. https://doi.org/10.1007/s10549-005-9053-3

Deng S. X. (1959). Diuretic and sedative effect of Divaricoside. Acta Pharm. Sin., 7, 161–165.

Dunn, D. E., He, D. N., Yang, P., Johansen, M., Newman, R. A., & Lo, D. C. (2011). In vitro and in vivo neuroprotective activity of the cardiac glycoside oleandrin from Nerium oleander in brain slice-based stroke models. J. Neurochem., 119(4), 805-814. https://doi.org/10.1111/j.1471-4159.2011.07439.x

Durlacher, C. T., Chow, K., Chen, X. W., He, Z. X., Zhang, X., Yang, T., & Zhou, S.F. (2015). Targeting Na+/ K+-translocating adenosine triphosphatase in cancer treatment. Clin. Exp. Pharmacol. Physiol., 42(5), 427–443. https://doi.org/10.1111/1440-1681.12385

Frese, S., Frese-Schaper, M., Andres, A.C., Miescher, D., Zumkehr, B., & Schmid, R. A. (2006). Cardiac glycosides initiate Apo2L/TRAIL-induced apoptosis in non-small cell lung cancer cells by up-regulation of death receptors 4 and 5. Cancer Res., 66(11), 5867–5874. https://doi.org/10.1158/0008-5472.CAN-05-3544

Garofalo, S., Grimaldi, A., Chece, G., Porzia, A., Morrone, S., Mainiero, F., D'Alessandro, G., Esposito, V., Cortese, B., Di-Angelantonio, S., Trettel, F., & Limatola, C. (2017). The glycoside oleandrin reduces glioma growth with direct and indirect effects on tumor cells. J Neurosci., 37(14), 3926-3939. https://doi.org/10.1523/JNEUROSCI.2296-16.2017

Gershenwald, J. E., Scolyer, R. A., Hess, K. R., Sondak, V. K., Long, G. V., Ross, M. I., Lazar, A. J., Faries, M. B., Kirkwood, J. M., McArthur, G. A., Haydu, L. E., Eggermont, A. M. M., Flaherty, K. T., Balch, C. M., & Thompson, J. F. (2017). Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J. Clin., 67(6), 472–492. https://doi.org/10.3322/caac.21409

Hartwell, J. L., & Abbott, B. J. (1969). Antineoplastic principles in plants: recent developments in the field. Adv. Pharmacol. Chemother., 7, 117–209. https://doi.org/10.1016/51054-3589(08)60561-x

Hung, K. C. (1999). The Pharmacology of Chinese Herbs, (2nd ed). Boca Raton: CRC Press Inc.

Huq, M. M., Jabbar, A., Rashid, M. A., & Hasan, C. M. (1999). A novel antibacterial and cardiac steroid from the roots of Nerium oleander. Fitoterapia, 70(1), 5–9. https://doi.org/10.1016/S0367-326X(98)00013-6

Kepp, O., Menger, L., Vacchelli, E., Adjemian, S., Martins, I., Ma, Y., Sukkurwala, A. Q., Michaud, M., Galluzzi, L., Zitvogel, L., & Kroemer, G. (2012). Anticancer activity of cardiac glycosides: At the frontier between cell-autonomous and immunological effects. Oncoimmunology, 1(9), 1640–1642. https://doi.org/10.4161/onci.21684

Ko, Y. S., Rugira, T., Jin, H., Park, S. W. & Kim, H. J. (2018). Oleandrin and its derivative odoroside A, both cardiac glycosides, exhibit anticancer effects by inhibiting invasion via suppressing the STAT-3 signaling pathway. Int. J. Mol. Sci., 19(11), E3350. https://doi.org/10.3390/ijms19113350

Kolkhof, P., Geerts, A., Schäfer, S., & Torzewski, J. (2010). Cardiac glycosides potently inhibit Creactive protein synthesis in human hepatocytes. Biochem. Biophys. Res. Commun., 394(1), 233–239. https://doi.org/10.1016/j.bbrc.2010.02.177

Kumar, A., De, T., Mishra, A., & Mishra A. K. (2013). Oleandrin: A cardiac glycosides with potent cytotoxicity. Pharmacogn. Rev., 7(14), 131–139. https://doi.org/10.4103/0973-7847.120512

Li, C. T., Deng, S. H., & Ho, G. B. (1964). Comparison of cardiotonic actions between oleandrin and digitoxin. Yao Xue Xue Bao, 11, 540 544.

Li, X. X., Wang, D. Q., Sui, C. G., Meng, F. D., Sun, S. L., Zheng, J., & Jiang, Y. H. (2020). Oleandrin induces apoptosis via activating endoplasmic reticulum stress in breast cancer cells. Biomed. Pharmacother., 124, 109852. https://doi.org/10.1016/j.biopha.2020.109852

Lin, Y., Ho, D. H., & Newman, R. A. (2010). Human tumor cell sensitivity to oleandrin is dependent on relative expression of Na+, K+- ATPase subunits. J. Exp. Ther. Oncol., 8(4), 271–286.

Ma, Y., Zhu, B., Liu, X., Yu, H., Yong, L., Liu, X., Shao, J., & Liu, Z. (2015). Inhibition of oleandrin on the proliferation show and invasion of osteosarcoma cells in vitro by suppressing Wnt/beta-catenin signaling pathway. J. Exp. Clin. Cancer Res., 34, 115. https://doi.org/10.1186/s13046-015-0232-8

Ma, Y., Zhu, B., Yong, L., Song, C., Liu, X., Yu, H., Wang, P., Liu, Z., & Liu, X. (2016). Regulation of intrinsic and extrinsic apoptotic pathways in osteosarcoma cells following oleandrin treatment. Int. J. Mol. Sci., 17(11), E1950. https://doi.org/10.3390/ijms17111950

Manna, S. K., Nand, K. S., Newman, R. A., Cisneros, A., & Aggarwal, B. B. (2000). Oleandrin suppresses activation of nuclear transcription factor- kappaB, activator protein-1 and c-Jun NH2-terminal kinase. Cancer Res., 60(14), 3838–3847.

Mans, D. R., da Rocha, A. B., & Schwartsmann, G. (2000). Anti-cancer drug discovery and development in Brazil: targeted plant collection as a rational strategy to acquire candidate anti-cancer compounds. Oncologist., 5(3), 185–198. https://doi.org/10.1634/theoncologist.5-3-185

McConkey, D. J., Lin, Y., Nutt, L. K., Ozel, H. Z., & Newman, R. A. (2000). Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen independent, metastatic human prostate adenocarcinoma cells. Cancer Res., 60(14), 3807–3812.

Nasu, S., Milas, L., Kawabe, S., Raju, U., & Newman, R. (2002). Enhancement of radiotherapy by oleandrin is a caspase-3 dependent process. Cancer Lett., 185(2), 145-151. https://doi.org/10.1016/s0304-3835(02)00263-x

Newman, R. A., Kondo, Y., Yokoyama, T., Dixon, S., Cartwright, C., Chan, D., Johansen, M., & Yang, P. (2007). Autophagic cell death of human pancreatic tumor cells mediated by oleandrin, a lipid-soluble cardiac glycoside. Integr. Cancer Ther., 6(4), 354-364. https://doi.org/10.1177/1534735407309623

Newman, R. A., Yang, P., Pawlus, A. D., & Block, K. I. (2008). Cardiac glycosides as novel cancer therapeutic agents. Mol. Interv., 8(1), 36–49. https://doi.org/10.1124/mi.8.1.8

Pan, L., Zhang, Y., Zhao, W., Zhou, X., Wang, C., & Deng, F. (2017). The cardiac glycoside oleandrin induces apoptosis in human colon cancer cells via the mitochondrial pathway. Cancer Chemother. Pharmacol., 80(1), 91-100. https://doi.org/10.1007/s00280-017-3337-2

Patel, S. (2016). Plant-derived cardiac glycosides: Role in heart ailments and cancer management. Biomed. Pharmacother., 84, 1036–1041. https://doi.org/10.1016/j.biopha.2016.10.030

Piccioni, F., Roman, B. R., Fischbeck, K. H., & Taylor, J. P. (2004). A screen for drugs that protect against the cytotoxicity of polyglutamine-expanded androgen receptor. Hum. Mol. Genet., 13(4), 437-446. https://doi.org/10.1093/hmg/ddh045

Pressley, T. A. (1996). Structure and function of the Na, K pump: Ten years of molecular biology. Miner. Electrolyte Metab., 22(5-6), 264–271.

Rajasekaran, S. A., Ball, W. J., Jr., Bander, N. H., Liu, H., Pardee, J. D., & Rajasekaran, A. K. (1999). Reduced expression of beta-subunit of Na+,K+-ATPase in human clear-cell renal cell carcinoma. J. Urol., 162(2), 574–580.

Rose, A. M., & Valdes, R. (1994). Understanding the sodium pump and its relevance to disease. Clin. Chem., 40(9), 1674–1685.

Schoner, W., & Scheiner-Bobis, G. (2007). Endogenous and exogenous cardiac glycosides: Their roles in hypertension, salt metabolism, and cell growth. Am. J. Physiol. Cell Physiol., 293(2), 509–536. https://doi.org/10.1152/ajpcell.00098.2007

Shiratori, O. (1967). Growth inhibitory effect of cardiac glycosides and aglycons on neoplastic cells: in vitro and in vivo studies. Gann., 58(6), 521–528.

Siegel, R. L., Miller, K. D., & Jemal, A. (2020). Cancer statistics, 2020. CA Cancer J. Clin., 70(1), 7-30. https://doi.org/10.3322/caac.21590

Smith, J. A., Madden, T., Vijjeswarapu, M., & Newman, R. A. (2001). Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU145 by Anvirzel and its cardiac glycoside component, oleandrin. Biochem. Pharmacol., 62(4), 469-472. https://doi.org/10.1016/s0006-2952(01)00690-6

Sreenivasan, Y., Raghavendra, P. B., & Manna, S. K. (2006). Oleandrin-mediated expression of Fas potentiates apoptosis in tumor cells. J. Clin. Immunol., 26(4), 308-322. https://doi.org/10.1007/s10875-006-9028-0

Stenkvist, B. (1999). Is digitalis a therapy for breast carcinoma?. Oncol. Rep., 6(3), 493–496. https://doi.org/10.3892/or.6.3.493

Szabuniewicz, M., Schwartz, W. L., McCrady, J. D., & Russell, L. H. (1972). Experimental oleander poisoning and treatment. Southwestern Vet., 25, 105-114.

Terzioglu-Usak, S., Nalli, A., Elibol, B., Ozek, E., & Hatiboglu, M. A. (2020). AnvirzelTM regulates cell death through inhibiting GSK-3 activity in human U87 glioma cells. Neurol. Res., 42(1), 68-75. https://doi.org/10.1080/01616412.2019.1709744

Trevisi, L., Visentin, B., Cusinato, F., Pighin, I., & Luciani, S. (2004). Antiapoptotic effect of ouabain on human umbilical vein endothelial cells. Biochem. Biophys. Res. Commun., 321(3), 716–721. https://doi.org/10.1016/j.bbrc.2004.07.027

Turan, N., Akgün-Dar, K., Kuruca, S. E., Kiliçaslan-Ayna, T., Seyhan, V. G., Atasever, B., Meriçli, F., & Carin, M. (2006). Cytotoxic effects of leaf, stem and root extracts of Nerium oleander on leukemia cell lines and role of the p-glycoprotein in this effect. J. Exp. Ther. Oncol., 6(1), 31–38.

Van Kanegan, M. J., He, D. N., Dunn, D. E., Yang, P., Newman, R. A., West, A. E., & Lo, D. C. (2014). BDNF mediates neuroprotection against oxygen-glucose deprivation by the cardiac glycoside oleandrin. J. Neurosci., 34(3), 963-968. https://doi.org/10.1523/JNEUROSCI.2700-13.2014

Watabe, M., Masuda, Y., Nakajo, S., Yoshida, T., Kuroiwa, Y., & Nakaya, K. (1996). The cooperative interaction of two different signaling pathways in response to bufalin induces apoptosis in human leukemia U937 cells. J. Biol. Chem., 271(24), 14067–14072. https://doi.org/10.1074/jbc.271.24.14067

Watabe, M., Kawazoe, N., Masuda, Y., Nakajo, S., & Nakaya, K. (1997). Bcl-2 protein inhibits bufalin-induced apoptosis through inhibition of mitogen-activated protein kinase activation in human leukemia U937 cells. Cancer Res., 57(15), 3097–3100.

Yeh, J. Y., Huang, W. J., Kan, S. F., & Wang, P. S. (2001). Inhibitory effects of digitalis on the proliferation of androgen dependent and independent prostate cancer cells. J. Urol., 166(5), 1937–1942. https://doi.org/10.1016/s0022-5347(05)65724-2

Yong, L., Ma, Y., Zhu, B., Liu, X., Wang, P., Liang, C., He, G., Zhao, Z., Liu, Z., & Liu, X. (2018).Oleandrin synergizes with cisplatin in human osteosarcoma cells by enhancing cell apoptosis through activation of the p38 MAPK signaling pathway. Cancer Chemother. Pharmacol., 82(6), 1009-1020. https://doi.org/10.1007/s00280-018-3692-7

Downloads

Published

2021-06-15

How to Cite

Eroğlu Güneş, C., Seçer Çelik, F., Seçme, M., & Kurar, E. . (2021). Oleandrin Activates Apoptosis and Inhibits Metastasis of A375 Human Melanoma Cells. Natural Products and Biotechnology, 1(1), 9–19. Retrieved from https://natprobiotech.com/index.php/natprobiotech/article/view/8

Issue

Section

Research Article