Pentagamavunon-0 (PGV-0) Enhance Cytotoxic Effect of Doxorubicin through Increasing of Apoptosis, Senescence and ROS Level on Triple Negative Breast Cancer 4T1

Ismanurrahman Hadi, Riris Istighfari Jenie, Edy Meiyanto

Abstract


TNBC, one of the sub type of breast cancers was widely known with high tumorigenic and poor prognosis than others. The development of combination agent (co-chemotherapy) with doxorubicin for chemotherapy of TNBC were carried out to decrease doxorubicin side effect and resistance in cancer. This present study aims to explore the co-chemotherapeutic properties of PGV-0 and investigate induction of doxorubicin on apoptosis, senescence and ROS against TNBC. 4T1 Cell line were used as a TNBC in vitro model. Cytotoxic measurement was performed using MTT assay resulting in IC50 values of 52 μM. Meanwhile, the combination of doxorubicin and PGV-0 showed synergistic effect which decreased cell viability of 4T1 better than single treatment of doxorubicin. Apoptosis analysis was performed using annexin V/PI assay indicated that the combination treatment of PGV-0 and doxorubicin increased apoptosis evidence. Senescence detection was carried out using senescence-associated-β galactosidase (SA-β-gal) assay. The results showed that a single treatment of PGV-0 induced cellular senescence and increased senescence cells in combination treatment. Moreover, DCFDA staining showed that PGV-0 increased ROS level at single treatment, whereas combination treatment increased ROS intracellular compared to the positive control of doxorubicin. Based on these results, PGV-0 has potential as a co-chemotherapeutic candidate on TNBC.

Keyword: 4T1, PGV-0, Co-chemotherapy, Cytotoxic, Senescence, Apoptosis, ROS


Full Text:

PDF

References


Bundscherer, A., Malsy, M., Lange, R., Hofmann, P., Metterlein, T., Graf, B.M. and Gruber, M., 2013, Cell Harvesting Method Influences Results of Apoptosis Analysis by Annexin V Staining, Anticancer Res., 33, 3201–3204.

Campisi, J., 2013, Aging, Cellular Senescence, and Cancer, Annu. Rev. Physiol., 75, 685–705. CrossRef

Da’i, M., Jenie, U.A., Am, S., Meiyanto, E. and Kawaichi, M., 2012, The Effect of PGV-1, PGV-0 and Curcumin on Protein Involve in G2-M Phase of Cell Cycle and Apoptosis on T47D Breast Cancer Cell Line, J. Ilmu Kefarmasian Indonesia, 10, 99–110.

Davalli, P., Mitic, T., Caporali, A., Lauriola, A. and D’Arca, D., 2016, ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases, Oxid. Med. Cell. Longev., 2016, 1–18. CrossRef

Eccles, M. and Li, C.G., 2012, Senescence Associated β-galactosidase Staining, Bio-Protoc., 2(16), e247. CrossRef

Eruslanov, E. and Kusmartsev, S., 2010, Identification of ROS using oxidized DCFDA and flow-cytometry, Methods Mol. Biol. Clifton NJ, 594, 57–72. CrossRef

Hanna, A.D., Lam, A., Tham, S., Dulhunty, A.F. and Beard, N.A., 2014, Adverse Effects of Doxorubicin and Its Metabolic Product on Cardiac RyR2 and SERCA2A, Mol. Pharmacol., 86(4), 438–449. CrossRef

Hermawan, A., Aditya, F., Sendy, J. and Muthi, I., 2011, PGV-0 And PGV-1 Increased Apoptosis Induction of Doxorubicin on MCF-7 breast Cancer Cells, Pharmacon, 12, 5.

Huang, L., Jiang, Y. and Chen, Y., 2017, Predicting Drug Combination Index and Simulating the Network-Regulation Dynamics by Mathematical Modeling of Drug-Targeted EGFR-ERK Signaling Pathway, Sci. Rep., 7, 40752. CrossRef

Koch, A., Tamez, P., Pezzuto, J. and Soejarto, D., 2005, Evaluation of plants used for antimalarial treatment by the Maasai of Kenya, J. Ethnopharmacol., 101(1-3), 95–99. CrossRef

Lakshmanan, I. and Batra, S.K., 2013, Protocol for Apoptosis Assay by Flow Cytometry Using Annexin V Staining Method, Bio-Protoc., 3.

Larasati, Y.A., Yoneda-Kato, N., Nakamae, I., Yokoyama, T., Meiyanto, E. and Kato, J., 2018, Curcumin targets multiple enzymes involved in the ROS metabolic pathway to suppress tumor cell growth, Sci. Rep., 8, 2039. CrossRef

Meiyanto, E., Putri, D.D.P., Susidarti, R.A., Murwanti, R., Sardjiman, Fitriasari, A., Husnaa, U., Purnomo, H. and Kawaichi, M., 2014, Curcumin and its analogues (PGV-0 and PGV-1) enhance sensitivity of resistant MCF-7 cells to doxorubicin through inhibition of HER2 and NF-kB activation, Asian Pac. J. Cancer Prev. APJCP, 15, 179–184.

Mosmann, T., 1983, Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays, J. Immunol. Methods, 65(1-2), 55–63. CrossRef

O’Reilly, E.A., Gubbins, L., Sharma, S., Tully, R., Guang, M.H.Z., Weiner-Gorzel, K., McCaffrey, J., Harrison, M., Furlong, F., Kell, M. and McCann, A., 2015, The fate of chemoresistance in triple negative breast cancer (TNBC), BBA Clin., 3, 257–275. CrossRef

Redza-Dutordoir, M. and Averill-Bates, D.A., 2016, Activation of apoptosis signalling pathways by reactive oxygen species. Biochim. Biophys, Acta BBA-Mol. Cell Res., 1863, 2977–2992. CrossRef

Tan, B.L. and Norhaizan, M.E., 2019, Curcumin Combination Chemotherapy: The Implication and Efficacy in Cancer, Molecules, 24(14), 2527. CrossRef

Wen, C., Fu, L., Huang, J., Dai, Y., Wang, B., Xu, G., Wu, L. and Zhou, H., 2019, Curcumin reverses doxorubicin resistance via inhibition the efflux function of ABCB4 in doxorubicin-resistant breast cancer cells, Mol. Med. Rep., 19, 5162–5168. CrossRef




DOI: http://dx.doi.org/10.14499/indonesianjcanchemoprev11iss1pp7-15

Copyright (c) 2020 Ismanurrahman Hadi, Riris Istighfari Jenie, Edy Meiyanto

Indexed by:

               

               

      

 

Indonesian Society for Cancer Chemoprevention