In Vitro Study of the Combination of Doxorubicin, Curcuma xanthorrhiza, Brucea javanica, and Ficus septica as a Potential Novel Therapy for Metastatic Breast Cancer

Ika Rahmawati Sutejo, Herwandhani Putri, Sri Handayani, Riris Istighfari Jenie, Edy Meiyanto

Abstract


Less optimized therapeutic effects constrain the use of doxorubicin as the main agent of chemotherapy for metastatic breast cancer, resistance and side effects. Therefore we need a combination of more than one chemopreventive agent which has different molecular targets to solve that problem. The aims of this study is to prove the inhibitory effect of ethanolic extract of rhizome of Curcuma xanthorrhiza (ECx), fruit of Brucea javanica (EBj), leave of Ficus septica (EFs) and doxorubicin (Dox) alone and its combination on migration and invasion of a highly metastatic 4T1 breast cancer cell line. Cytotoxic activity of single and combination treatment was evaluated by MTT assay, followed by an experiment of apoptosis induction by using flow cytometry. The inhibitory effect on migration was observed by the scratch wound-healing assay. Furthermore, the observation of the activity of matrix metalloproteinase-9 (MMP-9) was analyzed by gelatin zymography. The results showed that ECx, EBj, EFs, and Dox has cytotoxic activity on 4T1 cells with the value of IC50 respectively 49.7±1.53mg/mL, 59.9±1.79mg/mL, 15.2±2.12mg/mL and 1.2±0.23mM. Furthermore, combination of ECx-EBj-Dox and ECx-EBj-EFs revealed synergistic effect on 4T1 cells and decrease cell viability through the induction of apoptosis and necrosis. Based on wound healing assay, 24 hours incubation of this combination inhibited 4T1 cells migration compared to single treatment. Gelatin zymography analysis showed that this combination also inhibited the activity of MMP-9 greater than a single use. Curcuma xanthorrhiza, Brucea javanica, and Ficus septica may have potential to be developed as a combination with or without doxorubicin for metastatic breast cancer treatment.


Keywords


C xanthorrhiza, Bjavanica, F septica, antimetastasis, 4T1 cells

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References


Bandyopadhyay A., Wang L., Agyin J., Tang Y., Lin S., Yeh I., De K., and Sun L. 2010. Doxorubicin in combination with a small TGFβ inhibitor: a potential novel therapy for metastatic breast cancer in mouse models. Plos One, 5(4):e10365.

Bapsy PP., and Sahoo TP. 2004. Recent advances in the management of metastatic breast cancer, Indian Journal of Medical & Paediatric Oncology, 24 (2):19-26.

Chen M., Chen R., Wang S., Tan W., Hu Y., Peng X., and Wang Y. 2013. Chemical components, pharmacological properties, and nanoparticulate delivery systems of Brucea javanica, Int. J. nanomedicine, 8. 85-92. 10.2147/IJN.S31636.

Choi MA., Kim SH., Chung WY., Hwang JK., and Park KK. 2005. Xanthorrhizol, a natural sesquiterpenoid from Curcuma xanthorrhiza, has an anti-metastatic potential in experimental mouse lung metastasis model, Biochem. Biophys. Res. Commun., 326(1):210-7.

Engeland M., Nieland LJW., Ramaekers FCS., Schutte B., and Reutelingsperger CPM. 1998. Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure, Cytometry, 31:1-9.

Kim J., Lau EK., Pan L., and De Blanco EJC. 2010. NFB inhibitors from Brucea javanica exhibiting intracellular effect on reactive oxygen species, Anticancer res., 30: 3295-3300.

Krstic J., and Santibanez JF. 2014. Transforming growth factor-beta and matrix metalloproteinases: functional interaction in tumor stroma-infiltrating myeloid cells, The Scientific World Journal, 2014: 521754.

Kunnumakkara AB., Anand P., and Aggarwal B. 2008. Curcumin inhibits proliferation, invasion, angiogenesis & metastasis of different cancers through interaction with multiple cell signalling proteins, Cancer Letter 269: 199-225.

Kupai K. 2011. Gelatin zymography for detection of matrix-metalloproteinase-2 and -9 (mmp-2, mmp-9) from myocardial samples, Practical course: Basic biochemical methods and ischemic heart model (link:http://www3.szote.u-szeged.hu/hurodocs/hun/downloads/biochemistry/HURO_zymo_practical_Kupai_final.pdf.

Lewandowska U., Gorlach S., Owczarek K., Hrabec E., Szewczyk K. 2014. Synergistic interaction between anticancer chemotherapeutics and phenolic compounds and anticancer synergy between polyphenols, Postepy Hig Med Dosw (online), (68):528-540.

Liang C., Park AY., and Guan J. 2007. In vitro scratch assay: a convenient & inexpensive method for analysis of cell migration in vitro, Nature Protocol, 2 (2). Doi:10.1038/nprot.2007.30.

Lin HJ., Su CC., Lu HF., Yang JS., Hsu SC., and Ip SW. 2010. Curcumin blocks migration & invasion of mouse-rat hybrid retina ganglion cells (n 18) through the inhibition of MMP-2, -9, PAK, Rho A & Rock-1 Gene expression, Oncology Reports, 23: 665-670 DOI: 10.3892/or_00000682.

Mandhare AA., Dhulap SA., Dhulap AS., and Biradar SC. 2015. Review on the Anticancer and In-silico Binding Studies of Phenanthroindolizidine Alkaloids, ImedPub journal, Vol 1 No 1:5.

Mosmann T. 1983. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays, Journal of Immunological Methods, 65: 55-63.

Nan Z., Li YH., Wu XK., Wang GY., Cai DY., and Han FJ. 2015. Effect of Brucea javanica fruit oil emulsion combined cisplatin on the growth inhibition of transplanted tumor in human ovarian cancer SKOV3 nude mice: an experimental study. Zhongguo Zhong Xi Yi Jie He Za Zhi, 35 (1): 57-62.

Nie YL., Liy KX., Mao XY., Li YL, Li J., and Zhang MM. 2012. Effect of injection of Brucea javanica oil emulsion plus chemoradiotherapy for lung cancer: a review of clinical evidence, J Evid Based Med., 5(4):216-25.

Pratama RH., Ikhtiarsyah YG., Fitriasari A., Anindyajati Ikawati M., Meiyanto E. 2011. Awar-awar leaves ethanolic extract synergistically enhances cytotoxic of doxorubicin on T47D breast cancer cells, Ind J Pharm Sci., 9(1):67–71.

Reynolds CP., and Maurer BJ. 2005. Evaluating response to antineoplastic drug combinations in tissue culture models, Methods Mol Med., 110:173-83.

Sarkar FH., and Li Y. 2006. Using Chemopreventive agents to enhance the efficacy of cancer therapy, Cancer Rev., 66(7):3347-3350.

Sekti DA., Mubarok MF., Armandani I., Junedy S., and Meiyanto E. 2010. Awar-awar (Ficus septica Burm. F.) leaves ethanolic extract induced apoptosis of MCF-7 cells by downregulation of Bcl-2, J Trad Med., 15(3):100–104.

Smith LA., Cornelius VR., Plummer CJ., Levitt G., Verill M., Canney P., and Jones A. 2010. Cardiotoxicity of anthracycline agents for the treatment of cancer: Systematic Review & Meta-analysis of Randomised. BMC Cancer, 10:337.

Sugimoto K., Tamayose K., Sasaki M., Hayashi K., and Oshimi K. 2002. Low-dose doxorubicin-induced necrosis in Jurkat cells and its acceleration & conversion to apoptosis by antioxidants, British Journal of Haematology, 118:229-238. DOI: 10.1046/j.1365-2141.2002.03577.

Sugiyama T., and Sadzuka Y. 1999. Combination of theanine with doxorubicin inhibits hepatic metastasis of M5076 ovarian sarcoma, Clin. Cancer Res., 5, 413–416.

Tao K., Fang M., Alroy J., and Sahagian GG. 2008. Imagable 4T1 model for the study of late-stage breast cancer, BMC Cancer, 8:228.

Thangapazham RL., Sharma A., and Maheshwari RK. 2006. Multiple molecular targets in cancer chemoprevention by curcumin, The AAPS Journal, 8: E443.

Xinjie DU., and Linyi HE. 2013. The study on the expression effects of Brucea Javanica oil on VEGF and bFGF in proliferative endometrium hyperplasia of rats, Journal of Binzhou Medical University, 2013-01.




DOI: http://dx.doi.org/10.14499/indonesianjpharm30iss1pp15

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