The synergistic effect of doxorubicin and ethanolic extracts of Caesalpinia sappan L. wood and Ficus septica Burm. f. leaves on viability, cell cycle progression, and apoptosis induction of MCF­7 cells

https://doi.org/10.22146/ijbiotech.26105

Sari Haryanti(1), Suwijiyo Pramono(2), Retno Murwanti(3), Edy Meiyanto(4*)

(1) Balai Besar Penelitian dan Pengembangan Tanaman Obat dan Obat Tradisional, Kementerian Kesehatan Republik Indonesia, Tawangmangu
(2) Departement of Pharmaceutical Biology, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta
(3) Departement of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta
(4) Departement of Pharmaceutical Chemistry, and Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta
(*) Corresponding Author

Abstract


Caesalpinia sappan L. and Ficus septica Burm. f  known asa potential plant with wide variety of medicinal properties, including anticancer. Present study was aimed to explore cytotoxic effect ofsappan wood (ECS) and awar-awar leaves (EFS), and its combination with doxorubicin (dox) on MCF-7 cells focusing on cell cycle progression and apoptosis induction.The result of MTT assay showed that single treatment of ECS and dox performed cytotoxic effect with the IC50 value of 32 µg/mL and 6 µM respectively, while EFS performed low cytotoxic effect with the IC50 value of 282 µg/mL. The combination of ECS with EFS and doxorubicin showed synergistic cytotoxic effect. Flow cytometry analysis revealed that combination of ECS (16 µg/mL) with EFS (8 µg/mL) and doxorubicin (2 µM) induced apoptosis, and cell accumulation at sub-G1 and G2/M phases.Immunoblotting assay confirmed the apoptosis induction of this combination through increasing of cleavage of PARP-1. Based on these results, the synergistic cytotoxic effect of this combinationwas through G2/M phase accumulation and apoptosis inductionand potentially to be developed as co-chemotherapeutic agent.



Keywords


apoptosis; cell cycle; doxorubicin; Ficus septica leaves; MCF-7, sappan wood

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References

AbuHammad, S., Zihlif, M., 2013. Gene expression alterations in doxorubicin resistant MCF7 breast cancer cell line. Genomics 101, 213–220. doi:10.1016/j.ygeno.2012.11.009

Anampa, J., Makower, D., Sparano, J.A., 2015. Progress in adjuvant chemotherapy for breast cancer: an overview. BMC Med. 13, 195. doi:10.1186/s12916-015-0439-8

Asghar, U., Witkiewicz, A.K., Turner, N.C., Knudsen, E.S., 2015. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov. 14, 130–146. doi:10.1038/nrd4504

Barnum, K.J., O’Connell, M.J., 2014. Cell Cycle Regulation by Checkpoints. Methods Mol. Biol. Clifton NJ 1170, 29–40. doi:10.1007/978-1-4939-0888-2_2

Carrassa, L., 2013. Cell cycle, checkpoints and cancer. Atlas Genet. Cytogenet. Oncol. Haematol. doi:10.4267/2042/52080

Cathcart, J., Pulkoski-Gross, A., Cao, J., 2015. Targeting matrix metalloproteinases in cancer: Bringing new life to old ideas. Genes Dis. 2, 26–34. doi:10.1016/j.gendis.2014.12.002

Chemler, S., 2009. Phenanthroindolizidines and Phenanthroquinolizidines: Promising Alkaloids for Anti-Cancer Therapy. Curr. Bioact. Compd. 5, 2–19. doi:10.2174/157340709787580928

Chou, T.C., 2010. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res. 70, 440–446. doi:10.1158/0008-5472.CAN-09-1947

Deep, G., Agarwal, R., 2008. New Combination Therapies with Cell Cycle Agents. Curr. Opin. Investig. Drugs Lond. Engl. 2000 9, 591–604.

Dumontet, C., Jordan, M.A., 2010. Microtubule-binding agents: a dynamic field of cancer therapeutics. Nat. Rev. Drug Discov. 9, 790–803. doi:10.1038/nrd3253

Ghavami, S., Hashemi, M., Ande, S.R., Yeganeh, B., Xiao, W., Eshraghi, M., Bus, C.J., Kadkhoda, K., Wiechec, E., Halayko, A.J., Los, M., 2009. Apoptosis and cancer: mutations within caspase genes. J. Med. Genet. 46, 497–510. doi:10.1136/jmg.2009.066944

Hoesel, B., Schmid, J.A., 2013. The complexity of NF-κB signaling in inflammation and cancer. Mol. Cancer 12, 86. doi:10.1186/1476-4598-12-86

Kelley, M.R., Logsdon, D., Fishel, M.L., 2014. Targeting DNA repair pathways for cancer treatment: what’s new? Future Oncol. Lond. Engl. 10, 1215–1237. doi:10.2217/fon.14.60

Ko, E.Y., Moon, A., 2015. Natural Products for Chemoprevention of Breast Cancer. J. Cancer Prev. 20, 223–231. doi:10.15430/JCP.2015.20.4.223

Kummar, S., Chen, H.X., Wright, J., Holbeck, S., Millin, M.D., Tomaszewski, J., Zweibel, J., Collins, J., Doroshow, J.H., 2010. Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements. Nat. Rev. Drug Discov. 9, 843–856. doi:10.1038/nrd3216

Lal, S., Mahajan, A., Ning Chen, W., Chowbay, B., 2010. Pharmacogenetics of target genes across doxorubicin disposition pathway: a review. Curr. Drug Metab. 11, 115–128.

Meiyanto, E., Hermawan, A., Anindyajati, A., 2012. Natural Products for Cancer-Targeted Therapy: Citrus Flavonoids as Potent Chemopreventive Agents. Asian Pac. J. Cancer Prev. 13, 427–436. doi:10.7314/APJCP.2012.13.2.427

Mekala, K., Radha, R., 2015. A Review on Sappan Wood-A Therapeutic Dye Yielding Tree. Res. J. Pharmacogn. Phytochem. 7, 227. doi:10.5958/0975-4385.2015.00035.7

Nirmal, N.P., Rajput, M.S., Prasad, R.G.S.V., Ahmad, M., 2015. Brazilin from Caesalpinia sappan heartwood and its pharmacological activities: A review. Asian Pac. J. Trop. Med. 8, 421–430. doi:10.1016/j.apjtm.2015.05.014

Nugroho, A.E., Akbar, F.F., Wiyani, A., Sudarsono, 2015. Cytotoxic Effect and Constituent Profile of Alkaloid Fractions from Ethanolic Extract of Ficus septica Burm. f. Leaves on T47D Breast Cancer Cells. Asian Pac. J. Cancer Prev. APJCP 16, 7337–7342.

Nugroho, A.E., Hermawan, A., Putri, D.D.P., Novika, A., Meiyanto, E., 2013. Combinational effects of hexane insoluble fraction of Ficus septica Burm. F. and doxorubicin chemotherapy on T47D breast cancer cells. Asian Pac. J. Trop. Biomed. 3, 297–302. doi:10.1016/S2221-1691(13)60066-0

Nugroho, A.E., Ikawati, M., Hermawan, A., Putri, D.D.P., Meiyanto, E., 2011. Cytotoxic Effect of Ethanolic Extract Fractions of Indonesia Plant Ficus septica Burm. F. on Human Breast Cancer T47D cell lines. Int. J. Phytomedicine 3, 216–226.

Nurzijah, I., Putri, D.D.P., Rivanti, E., Meiyanto, E., 2012. Secang (Caesalpinia sappan L.) Heartwood Ethanolic Extract Shows Activity as Doxorubicin Co-chemotherapeutic Agent by Apoptotis Induction on T47D Breast Cancer Cells 3, 377–384.

Santarpia, L., Lippman, S.L., El-Naggar, A.K., 2012. Targeting the Mitogen-Activated Protein Kinase RAS-RAF Signaling Pathway in Cancer Therapy. Expert Opin. Ther. Targets 16, 103–119. doi:10.1517/14728222.2011.645805

Sekti, D.A., Mubarok, M.F., Armandani, I., Junedy, S., Meiyanto, E., 2010. Ekstrak etanolik daun awar-awar (Ficus septica Burm. f.) memacu apoptosis sel kanker payudara MCF-7 melalui penekanan ekspresi Bcl-2. Maj. Obat Tradis. 15, 100–104.

Takeuchi, K., Ito, F., 2011. Receptor tyrosine kinases and targeted cancer therapeutics. Biol. Pharm. Bull. 34, 1774–1780.

Tuorkey, M.J., 2014. Curcumin a potent cancer preventive agent: Mechanisms of cancer cell killing. Interv. Med. Appl. Sci. 6, 139–146. doi:10.1556/IMAS.6.2014.4.1

Vejpongsa, P., Yeh, E.T.H., 2014. Prevention of Anthracycline-Induced Cardiotoxicity: Challenges and Opportunities. J. Am. Coll. Cardiol. 64, 938–945. doi:10.1016/j.jacc.2014.06.1167

Wang, Z., Wang, F., Tang, T., Guo, C., 2012. The role of PARP1 in the DNA damage response and its application in tumor therapy. Front. Med. 6, 156–164. doi:10.1007/s11684-012-0197-3

Weaver, A.N., Yang, E.S., 2013. Beyond DNA Repair: Additional Functions of PARP-1 in Cancer. Front. Oncol. 3. doi:10.3389/fonc.2013.00290

Witsch, E., Sela, M., Yarden, Y., 2010. Roles for Growth Factors in Cancer Progression. Physiol. Bethesda Md 25, 85–101. doi:10.1152/physiol.00045.2009

Wong, R.S., 2011. Apoptosis in cancer: from pathogenesis to treatment. J. Exp. Clin. Cancer Res. 30, 1–14. doi:10.1186/1756-9966-30-87



DOI: https://doi.org/10.22146/ijbiotech.26105

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