Anticancer Effects of Cisplatin and 6-Gingerol Co-Treatment on MDA-MB-231 Breast Cancer Cells
DOI:
https://doi.org/10.11113/jomalisc.v3.80Keywords:
Cisplatin, 6-gingerol, combination therapy, cisplatin, 6-gingerol, combination therapy, triple-negative breast cancer (TNBC)Abstract
Breast cancer is known to be a common cancer diagnosed by people around the world, and a high number of breast cancer cases are recorded annually. Triple-negative breast cancer (TNBC), the most aggressive form of breast cancer, is often difficult to treat as it lacks expression of estrogen, progesterone and human epidermal growth factor receptors that are often targeted for other breast cancer subtypes. Hence, chemotherapy remains the main option to treat TNBC. Cisplatin, a powerful anticancer drug, is commonly used as a chemotherapeutic agent for TNBC treatment. Nevertheless, the development of chemoresistance and adverse side effects observed in clinics limit the use of cisplatin in treating cancer. Various studies have shown that cisplatin, in combination with plant-based compounds, has successfully reduced its toxicity as well as tumour resistance to its treatment. Recent findings have shown that 6-gingerol, the major phytochemical in ginger, possesses excellent anticancer properties. Therefore, this study reports the anticancer effects of cisplatin, 6-gingerol and cisplatin-6-gingerol co-treatment on the cell viability and changes in morphology of MDA-MB-231 breast cancer cells, which represents the TNBC subtype. Alamar Blue assay was performed to study cell viability while morphological changes in cells before and after treatments were observed via microscopy imaging. In addition, the drug-drug interaction was studied via the CompuSyn software. The IC50 concentrations of cisplatin, 6-gingerol and combined cisplatin-6-gingerol treatments were achieved at 8.08mM, 80.24mM and 58.53mM, respectively. In the combined therapy, a reduced cisplatin concentration (5mM) was used with 0-100 mM 6-gingerol.The combination therapy required a lower dosage of both agents (5mM cisplatin in combination with 58.53mM 6-gingerol) to inhibit 50% of MDA-MB-231 cell growth. Both solo and combined treatments reduced the cell viability of MDA-MB-231 effectively in a dose-dependent manner but with different capacities. Morphological changes of MDA-MB-231 cells upon each treatment suggested that each treatment could induce different cell fate. However, the analyzed drug-drug interaction between 5 mM cisplatin and 0-100 mM 6-gingerol on MDA-MB-231 cells revealed that the combined treatment exerted an antagonistic effect. It is presumed that the cisplatin concentration used counteracted with the effect of 6-gingerol, consequently affecting the overall inhibitory effect in MDA-MB-231 cells. In conclusion, the present study shows that solo treatment of cisplatin and 6-gingerol, respectively, had a more significant inhibitory effect compared to the co-treatment on MDA-MB-231 breast cancer cells. However, further studies are required to examine the combined effect of cisplatin and 6-gingerol using different combination strategies for more promising outcomes that can provide valuable knowledge in contributing to TNBC treatment management.
References
Bakar, N. F. a. B. A., Yeo, Z. L., Hussin, F., Madhavan, P., Lim, V., Jemon, K., & Prabhakaran, P. (2023). Synergistic effects of combined cisplatin and Clinacanthus nutans extract on triple negative breast cancer cells. Journal of Taibah University Medical Sciences, 18(6), 1220–1236. https://doi.org/10.1016/j.jtumed.2023.04.003
Balvan, J., Krizova, A., Gumulec, J., Raudenska, M., Sladek, Z., Sedlackova, M., Babula, P., Sztalmachova, M., Kizek, R., Chmelik, R., & Masarik, M. (2015). Multimodal Holographic Microscopy: Distinction between Apoptosis and Oncosis. PLoS ONE, 10(3), e0121674. https://doi.org/10.1371/journal.pone.0121674
Bisht, S., Nigam, M., Kunjwal, S. S., Sergey, P., Mishra, A. P., & Sharifi-Rad, J. (2022). Cancer Stem Cells: From an Insight into the Basics to Recent Advances and Therapeutic Targeting. Stem Cells International, 2022, 1–28. https://doi.org/10.1155/2022/9653244
Cesna, V., Sukovas, A., Jasukaitiene, A., Naginiene, R., Barauskas, G., Dambrauskas, Z., Paskauskas, S., & Gulbinas, A. (2018). Narrow line between benefit and harm: Additivity of hyperthermia to cisplatin cytotoxicity in different gastrointestinal cancer cells. World Journal of Gastroenterology, 24(10), 1072–1083. https://doi.org/10.3748/wjg.v24.i10.1072
Dasari, S., Njiki, S., Mbemi, A., Yedjou, C. G., & Tchounwou, P. B. (2022). Pharmacological Effects of Cisplatin Combination with Natural Products in Cancer Chemotherapy. International Journal of Molecular Sciences, 23(3), 1532. https://doi.org/10.3390/ijms23031532
E, E. S., Z, E., A, H. A., N, M., M, E., & E, O. (2020). Possible Protective Role of Sodium Salicylate Nanoemulsion and Ginger on Cisplatin‐Induced Hepatotoxicity in Rats (Biochemical And Histopathological Study). International Journal of Current Pharmaceutical Research, 133–139. https://doi.org/10.22159/ijcpr.2020v12i3.38323
Furlanetto, J., & Loibl, S. (2020). Optimal systemic treatment for early Triple-Negative breast cancer. Breast Care, 15(3), 217–226. https://doi.org/10.1159/000508759
Garg, A. P. (2023). Identification of Gingerol (6-Gingerol) as Humming Inhibitor of Cancer through Docking Analysis. www.jscimedcentral.com. https://doi.org/10.47739/1091
Ghosh, S. (2019). Cisplatin: The first metal based anticancer drug. Bioorganic Chemistry, 88, 102925. https://doi.org/10.1016/j.bioorg.2019.102925
Gupta, G. K., Collier, A. L., Lee, D. H., Hoefer, R., Zheleva, V., Van Reesema, L. L. S., Tang-Tan, A. M., Guye, M. L., Chang, D. Z., Winston, J. S., Şamli, B., Jansen, R., Petricoin, E. F., Goetz, M. P., Bear, H. D., & Tang, A. (2020). Perspectives on Triple-Negative Breast Cancer: current treatment strategies, unmet needs, and potential targets for future therapies. Cancers, 12(9), 2392. https://doi.org/10.3390/cancers12092392
Ibrahim, A. S., Sobh, M., Eid, H. M., Salem, A., Elbelasi, H. H., ElNaggar, M. H., Abdelbar, F. M., Sheashaa, H., Sobh, M., & Badria, F. A. (2014). Gingerol-derivatives: emerging new therapy against human drug-resistant MCF-7. Tumor Biology, 35(10), 9941–9948. https://doi.org/10.1007/s13277-014-2248-7
Kapoor, V., Aggarwal, S., & Das, S. N. (2016). 6‐Gingerol Mediates its Anti Tumor Activities in Human Oral and Cervical Cancer Cell Lines through Apoptosis and Cell Cycle Arrest. PTR. Phytotherapy Research/Phytotherapy Research, 30(4), 588–595. https://doi.org/10.1002/ptr.5561
Kim, C., Gonye, A. L., Truskowski, K., Lee, C., Cho, Y., Austin, R. H., Pienta, K. J., & Amend, S. R. (2023). Nuclear morphology predicts cell survival to cisplatin chemotherapy. Neoplasia, 42, 100906. https://doi.org/10.1016/j.neo.2023.100906
Kotowski, U., Kadletz, L., Schneider, S., Foki, E., Schmid, R., Seemann, R., Thurnher, D., & Heiduschka, G. (2017). 6‐shogaol induces apoptosis and enhances radiosensitivity in head and neck squamous cell carcinoma cell lines. Phytotherapy Research, 32(2), 340–347. https://doi.org/10.1002/ptr.5982
Lucero, M., Thind, J., Sandoval, J., Senaati, S., Jimenez, B., & Kandpal, R. P. (2020). Stem-like Cells from Invasive Breast Carcinoma Cell Line MDA-MB-231 Express a Distinct Set of Eph Receptors and Ephrin Ligands. Cancer Genomics & Proteomics, 17(6), 729–738. https://doi.org/10.21873/cgp.20227
Meng, L. (2023). Chromatin-modifying enzymes as modulators of nuclear size during lineage differentiation. Cell Death Discovery, 9(1). https://doi.org/10.1038/s41420-023-01639-z
Orrantia-Borunda, E., Anchondo-Nuñez, P., Acuña-Aguilar, L. E., Gómez-Valles, F. O., & Ramírez-Valdespino, C. A. (2022). Subtypes of breast cancer. In Exon Publications eBooks (pp. 31–42). https://doi.org/10.36255/exon-publications-breast-cancer-subtypes
Prabhakaran, P., Hassiotou, F., Blancafort, P., & Filgueira, L. (2013). Cisplatin induces differentiation of breast cancer cells. Frontiers in Oncology, 3. https://doi.org/10.3389/fonc.2013.00134
Prat, A., Parker, J. S., Karginova, O., Fan, C., Livasy, C., Herschkowitz, J. I., He, X., & Perou, C. M. (2010). Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Research, 12(5). https://doi.org/10.1186/bcr2635
Rastogi, N., Duggal, S., Singh, S. K., Porwal, K., Srivastava, V. K., Maurya, R., Bhatt, M. L., & Mishra, D. P. (2015). Proteasome inhibition mediates p53 reactivation and anti-cancer activity of 6-Gingerol in cervical cancer cells. Oncotarget, 6(41), 43310–43325. https://doi.org/10.18632/oncotarget.6383
Ray, R., Khashali, H. A., Haddad, B., Wareham, J., Coleman, K., Alomari, D., Ranzenberger, R., Guthrie, J., Heyl, D., & Evans, H. G. (2022). Regulation of cisplatin resistance in lung cancer cells by nicotine, BDNF, and a Β-Adrenergic receptor blocker. International Journal of Molecular Sciences, 23(21), 12829. https://doi.org/10.3390/ijms232112829
Rehman, M. U., Ahmad, B., Arif, A., Rasool, S., Farooq, A., Razzaq, R., Bhat, S. A., Bashir, S., Shabir, O., Amin, I., Masoodi, M., Mir, M. U. R., & Shah, M. Y. (2015). Zingerone protects against cisplatin-induced oxidative damage in the jejunum of Wistar rats. Oriental Pharmacy and Experimental Medicine/Oriental Pharmacy and Experimental Medicine, 15(3), 199–206. https://doi.org/10.1007/s13596-015-0187-5
Rodea-Palomares, I., González-Pleiter, M., Martín-Betancor, K., Rosal, R., & Fernández-Piñas, F. (2015). Additivity and interactions in ecotoxicity of pollutant mixtures: Some patterns, conclusions, and open questions. Toxics, 3(4), 342–369. https://doi.org/10.3390/toxics3040342
Salari, Z., Khosravi, A., Pourkhandani, E., Molaakbari, E., Salarkia, E., Keyhani, A., Sharifi, I., Tavakkoli, H., Sohbati, S., Dabiri, S., Ren, G., & Shafie’ei, M. (2023). The inhibitory effect of 6-gingerol and cisplatin on ovarian cancer and antitumor activity: In silico, in vitro, and in vivo. Frontiers in Oncology, 13. https://doi.org/10.3389/fonc.2023.1098429
Shahshahan, Z., Khosravi, A., Pourkhandani, E., Molaakbari, E., Salarkia, E., Keyhani, A., Sharifi, I., Tavakkoli, H., Sohbati, S., Dabiri, S., Ren, G., & Shafie’ei, M. (2023). The inhibitory effect of 6-gingerol and cisplatin on ovarian cancer and antitumor activity: In silico, in vitro, and in vivo. Frontiers in Oncology, 13. https://doi.org/10.3389/fonc.2023.1098429
Singh, L., Aldosary, S., Saeedan, A. S., Ansari, M. N., & Kaithwas, G. (2018). Prolyl hydroxylase 2: a promising target to inhibit hypoxia-induced cellular metabolism in cancer cells. Drug Discovery Today, 23(11), 1873–1882. https://doi.org/10.1016/j.drudis.2018.05.016
Sp, N., Kang, D. Y., Lee, J., Bae, S. W., & Jang, K. (2021). Potential antitumor effects of 6-Gingerol in P53-Dependent mitochondrial apoptosis and inhibition of tumor sphere formation in breast cancer cells. International Journal of Molecular Sciences, 22(9), 4660. https://doi.org/10.3390/ijms22094660
Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians, 71(3), 209–249. https://doi.org/10.3322/caac.21660
Wang, Q., Wei, Q., Yang, Q., Cao, X., Li, Q., Shi, F., Tong, S., Feng, C., Yu, Q., Yu, J., & Xu, X. (2018). A novel formulation of [6]-gingerol: Proliposomes with enhanced oral bioavailability and antitumor effect. International Journal of Pharmaceutics, 535(1–2), 308–315. https://doi.org/10.1016/j.ijpharm.2017.11.006
Xu, Y., Wang, Q., Feng, Y., Firempong, C. K., Zhu, Y., Omari-Siaw, E., Zheng, Y., Pu, Z., Xu, X., & Yu, J. (2016). Enhanced oral bioavailability of [6]-Gingerol-SMEDDS: Preparation, in vitro and in vivo evaluation. Journal of Functional Foods, 27, 703–710. https://doi.org/10.1016/j.jff.2016.10.007
Yang, L., Zha, L., Luo, L., Chen, X., Zhang, Q., Gao, C., Zhuang, X., Yuan, S., & Qiao, T. (2019). [6]‐Gingerol enhances the cisplatin sensitivity of gastric cancer cells through inhibition of proliferation and invasion via PI3K/AKT signaling pathway. Phytotherapy Research, 33(5), 1353–1362. https://doi.org/10.1002/ptr.6325
Yao, Y., Chu, Y., Xu, B., Hu, Q., & Song, Q. (2019). Radiotherapy after surgery has significant survival benefits for patients with triple‐negative breast cancer. Cancer Medicine, 8(2), 554–563. https://doi.org/10.1002/cam4.1954
Yu, K., Ye, F., He, M., Fan, L., Ma, D., Mo, M., Wu, J., Li, G., Di, G. H., Zeng, X., He, P., Wu, K., Hou, Y., Wang, J., Wang, C., Zhuang, Z., Song, C., Lin, X., Toss, A., . . . Shao, Z. (2020). Effect of adjuvant paclitaxel and carboplatin on survival in women with Triple-Negative breast Cancer. JAMA Oncology, 6(9), 1390. https://doi.org/10.1001/jamaoncol.2020.2965
Zhang, L., Chen, W., Liu, S., & Chen, C. (2023). Targeting breast cancer stem cells. International Journal of Biological Sciences, 19(2), 552–570. https://doi.org/10.7150/ijbs.76187
