Abstract
DLBS1425 is a bioactive compound extracted from Phaleria macrocarpa, with anti-proliferative, anti-inflammatory and anti-angiogenic properties against cancer cells. The present study was aimed to assess cardiotoxicity of DLBS1425, compared to the mainstay regimen for breast cancer, 5-fluorouracil:doxorubicin:cyclophosphamide (FAC, given at 500/50/500 mg/m2). Treatment with FAC regimen at standard dose resulted in very severe toxicity, so mice had no chance to survive for more than 7 days following initial drug treatment. Furthermore, histological examination on the heart revealed severe muscular damage when mice were given the FAC regimen alone (severe toxicity). FAC as chemotherapeutic regimen exerted high toxicity profile to the cardiovascular cells in this experiment. Meanwhile, treatment with DLBS1425 alone up to a dose equivalent to as high as 300 mg three times daily in human had no hazardous consequences on the heart, hematological feature, as well as general safety. In the cardiovascular cells, DLBS1425 in the presence of FAC regimen (one-eight of the initial dose) gave protection to the cardiac muscle cells as well as other hematological features. Taken together, results of the present study suggest that DLBS1425 is safe when used as adjuvant therapy for breast cancer and may be even protective against cardiac cellular damage produced by chemotherapeutic regimen.
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Parkin, D. M., Pisani, P., & Ferlay, J. (1999). Global cancer statistic. CA: A Cancer Journal for Clinicians, 49, 33–64.
NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Ver.2. 2011. NCCN Guidelines. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed March 11, 2014.
Podesta, A., Torre, P. E., Pincirolli, G., Iatropoulos, M. J., Brughera, M., & Mazue, G. (1994). Evaluation of 4’-Iodo-4’-deooxydoxorubicin-induced cardiotoxicity in two experimental rats models. Toxicologic Pathology, 22(1), 68–71.
Pouna, P., Bonoron-Adele, S., Gouverneur, G., Tariosse, L., Besse, P., & Robert, J. (1996). Development of the model of rat isolated perfused heart for the evaluation of anthracycline cardiotoxicity and its circumvention. British Journal of Pharmacology, 117, 1593–1599.
Li, K., Sung, R. Y., Huang, W. Z., Yang, M., Pong, N. H., Lee, S. M., et al. (2006). Thrombopoietin protects against in vitro and in vivo cardiotoxicity induced by doxorubicin. Circulation, 113(18), 2211–2220.
Mayer, L. D., Tai, L. C. L., Ko, D. S. C., Masin, D., Ginsberg, R. S., Cullis, P. R., et al. (1989). Influence of vesicle size, lipid composition and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice. Cancer Research, 49, 5922–5930.
Bally, M. B., Nayar, R., Masin, D., Cullis, P. R., & Mayer, L. D. (1990). Studies on the myelosuppressive activity of doxorubicin entrapped in liposomes. Cancer Chemotherapy and Pharmacology, 27, 13–19.
Tandrasasmita, O. M., Lee, J. S., Baek, S. H., & Tjandrawinata, R. R. (2010). Induction of cellular apoptosis in human breast cancer by DLBS1425, a Phaleria macrocarpa compound extract, via downregulation of PI3-kinase/AKT pathway. Cancer Biology & Therapy, 10(8), 1–11.
Tjandrawinata, R. R., Arifin, P. Z., Tandrasasmita, O. M., Rahmi, D., & Aripin, A. (2010). DLBS1425, a Phaleria macrocarpa (Scheff.) Boerl. extract confers anti-proliferative and pro-apoptosis effects via eicosanoid pathway. Journal of Experimental Therapeutics & Oncology, 8, 187–201.
Martin, M., Villar, A., Sole-Calvo, A., Gonzalez, R., Massuti, B., Lizon, J., et al. (2003). Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Annals of Oncology, 14, 833–842.
Kerrn, M. A., Haugg, A. M., & Koch, A. F. (2006). Cyclooxygenase-2 inhibition induces apoptosis signaling via death receptors and mitochondria in hepatocellular carcinoma. Cancer Research, 66(14), 7059–7066.
Bakhle, Y. S. (2001). COX-2 and cancer: A new approach to an old problem. British Journal of Pharmacology, 134, 1137–1150.
Chun, K.-S., Keum, Y.-S., Han, S. S., Song, Y.-S., Kim, S.-H., & Surh, Y.-J. (2003). Curcumin inhibits phorbol ester-induced expression of cyclooxygenase-2 in mouse skin through suppression of extracellular signal-regulated kinase activity and NF-kappa B activation. Carcinogenesis, 24, 1515–1524.
Tjandrawinata, R. R., Dahiya, R., & Hughes-Fulford, M. (1997). Induction of cyclooxygenase-2 mRNA by prostaglandin E2 in human prostatic carcinoma cells. British Journal of Cancer, 75, 1111–1118.
Tjandrawinata, R. R., & Hughes-Fulford, M. (1997). Up-regulation of cyclooxygenase-2 by product-prostaglandin E2. Advances in Experimental Medicine and Biology, 407, 163–170.
Howe, L. R., Subbaraimmaiah, K., Brown, A. M. C., & Dannenberg, A. J. (2001). Cyclooxygenase-2: A target for the prevention and treatment of breast cancer. Endocrine-Related Cancer, 8, 97–114.
Half, E., Tang, X. M., Gwyn, K., Sahin, A., Wathen, K., & Sinicrope, F. A. (2002). Cyclooxygenase-2 expression in human breast cancers and adjacent ductal carcinoma in situ. Cancer Research, 62, 1676–1681.
Basu, G. D., Pahangeny, L. B., Tinder, T. L., Gendler, S. J., & Mukherjee, P. (2005). Mechanism underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells. Breast Cancer Research, 7, R422–R435.
Billingham, M. E., Mason, J. W., Bristow, M. R., & Daniels, J. R. (1978). Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treatment Reports, 62, 865–872.
Aebi, H. (1974). Catalase in Methods of Enzymatic Analysis (Bergmeyer, H.U., ed.), Chemic Academic Press Inc., Verlag, pp.673-682.
Davies, K. J., & Doroshow, J. H. (1986). Redox cycling of anthracyclines by cardiac mitochondria: Anthracycline radical formation by NADPH dehydrogenous. Journal of Biological Chemistry, 261, 3060–3067.
Xu, X., Persson, H. L., & Richardson, D. R. (2005). Molecular pharmacology of the interaction of anthracyclines with iron. Molecular Pharmacology, 68(2), 261–271.
Sugioka, K., & Nakano, M. (1982). Mechanism of phospholipid peroxidation induced by ferric ion-ADP-adriamycin co-ordination complex. BBA-Lipids and Lipid Metabolism, 713(2), 333–343.
Singla, D. K., Ahmed, A., Singla, R., & Yan, B. (2012). Embryonic stem cells improve cardiac function in doxorubicin-induced cardiomyopathy mediated through multiple mechanisms. Cell Transplantation, 21(9), 1919–1930.
Torres, V. M. & Simic, V. D. (2012). Doxorubicin-induced oxidative injury of cardiomyocytes—Do we have right strategies for prevention?. In Cardiotoxicity of Oncologic Treatments (Fiuza, M., ed.), www.intechopen.com, CC BY 3.0 license, pp.89-130.
Hill, J. W., Cong, Z., Hess, G., McGarvey, N., & Nordyke, R. J. (2012). Hemoglobin decline in chemotherapy patients prior to and after policy changes affecting use of erythropoiesis-stimulating agents. Journal of International Medical Research, 40(4), 1532–1545.
Platt, O. S. (1985). Chemotherapy to increase fetal hemoglobin in patients with sickle cell anemia. The American Journal of Pediatric Hematology/Oncology, 7(3), 258–260.
Saad, S. Y., Najjar, T. A., & Alashari, M. (2004). Cardiotoxicity of doxorubicin/paclitaxel combination in rats: Effect of sequence and timing of administration. Journal of Biochemical and Molecular Toxicology, 18(2), 78–86.
Acknowledgments
We thank to Audrey Clarissa and Sherly Juliani for critical review on this manuscript. All authors disclosed receipt of the following financial supports from PT Dexa Medica to conduct this study.
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The author(s) declared no conflicts of interest with respect to the authorship and/or publication.
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Anggadiredja, K., Tjandrawinata, R.R. Cardiovascular Effects of Phaleria macrocarpa Extracts Combined with Mainstay FAC Regimen for Breast Cancer. Cardiovasc Toxicol 15, 90–99 (2015). https://doi.org/10.1007/s12012-014-9275-x
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DOI: https://doi.org/10.1007/s12012-014-9275-x