Sains Malaysiana 53(8)(2024): 1981-1991
http://doi.org/10.17576/jsm-2024-5308-20
Cytotoxic
Effect of Clinacanthus nutans Semi-purified Fraction (SF1) in Combination with
Cisplatin against Human Cervical Cancer
(Kesan Sitotoksik Fraksi Separa Tulen (SF1) Clinacanthus nutans dalam Gabungan dengan Cisplatin terhadap Kanser Pangkal Rahim Manusia)
NUR FATIN NAJIHAH MARZUKI1, YUSMAZURA ZAKARIA1,*, MARYAM AZLAN1 & NIK FAKHURUDDIN NIK HASSAN2
1Biomedicine
Programme, School of Health Sciences, Health Campus, Universiti Sains Malaysia, 16150 Kota Bharu,
Kelantan, Malaysia
2Forensic
Science Programme, School of Health Sciences, Health Campus, Universiti Sains Malaysia, 16150
Kota Bharu, Kelantan, Malaysia
Diserahkan: 15 Oktober 2023/Diterima:
12 Jun 2024
Abstract
Cervical cancer is one of the most diagnosed malignancies in the world,
and it is associated with HPV virus infection and invasion. A standard fraction
from the medicinal plant Clinacanthus nutans was successfully separated, isolated, and
identified as SF1 (semi-purified fraction). According to the previous study,
SF1 has shown cytotoxic action against the cervical cancer cell line, SiHa. This study aims to further annotate the effect of SF1
in combination with cisplatin against SiHa to
increase the selectivity of the anti-cancer treatment. The MTT assay was used
to analyse the combination treatment's cytotoxicity, and its index value was
calculated using the Chou-Talalay method. A cell
survival test was conducted to evaluate the reproducibility of cancer cells
after being treated. The combination treatment has enhanced cytotoxic action
and inhibited SiHa’s cell proliferation the most (IC50 value = 5.10 ± 0.86 μg/mL) compared to the
individual cytotoxic activity of SF1 (IC50 value = 9.60 ± 0.20
µg/mL) and cisplatin (IC50 value = 3.60 ± 0.60 μg/mL).
Simultaneously, the combination study has shown lesser cytotoxic activity
towards normal cells, Vero (IC50 value = 10.30 ± 3.10 μg/mL) compared to SiHa cells. The combination also showed an antagonism effect with CI values of 2.60
to 1.50 and fractional inhibition (Fa) of 0.50 to 0.90. The findings have
demonstrated that in contrast with single-agent therapy, the treatment of
SF1 and cisplatin in combination has increased the efficacy because it
selectively targets cancer cells by antagonism action.
Keywords: Antagonism; Clinacanthus nutans; cisplatin; cytotoxicity; SiHa
Abstrak
Kanser pangkal rahim adalah salah satu kanser yang paling banyak didiagnosis di dunia dan ia dikaitkan dengan jangkitan dan pencerobohan virus HPV. Fraksi daripada tumbuhan ubatan Clinacanthus nutans berjaya dipisahkan, diasingkan dan dikenal pasti sebagai SF1 (fraksi separa – penulenan). SF1 telah menunjukkan tindakan sitotoksik terhadap titisan sel kanser pangkal rahim, SiHa menurut kajian terdahulu. Kajian kali ini bertujuan untuk menjelaskan lagi kesan SF1 dalam penggabungan dengan cisplatin terhadap SiHa untuk meningkatkan selektiviti untuk rawatan anti kanser. Asai MTT digunakan untuk menganalisis sitotoksisiti rawatan gabungan dan nilai indeks gabungannya dihitung menggunakan kaedah Chou-Talalay. Ujian kemandirian sel telah dijalankan untuk menilai kebolehulangan sel kanser selepas dirawat. Rawatan gabungan telah meningkatkan tindakan sitotoksik dan menghalang pembiakan sel SiHa paling banyak (nilai IC50 = 5.10 ± 0.86 μg/mL) berbanding tindakan sitotoksik secara individu SF1 (nilai IC50 = 9.60 ± 0.20 μg/mL) dan cisplatin (nilai IC50 = 3.60 ± 0.60 μg/mL). Pada masa yang sama, kajian gabungan telah menunjukkan tindakan sitotoksik yang lebih rendah terhadap sel normal, Vero (nilai IC50 = 10.30 ± 3.10 μg/mL) berbanding sel SiHa. Gabungan tersebut juga menunjukkan kesan antagonis dengan nilai CI 2.60 hingga 1.50 dengan perencatan pecahan (Fa) 0.50 hingga 0.90. Penemuan telah menunjukkan bahawa berbeza dengan terapi agen tunggal, rawatan gabungan SF1 dan cisplatin telah meningkatkan keberkesanan kerana ia secara selektif menyasarkan sel-sel kanser melalui tindakan antagonisme.
Kata kunci: Antagonisme; cisplatin; Clinacanthus nutans; SiHa; sitotoksiksiti
RUJUKAN
Ali, R., Aouida, M., Sulaiman, A.A. & Madhusudan, S. 2022. Can
cisplatin therapy be improved ? Pathways that can be targeted. International
Journal of Molecular Sciences 23(13): 7241.
Arbyn, M., Weiderpass, E., Bruni, L., de Sanjosé, S., Saraiya, M., Ferlay,
J. & Bray, F. 2020. Estimates of incidence and mortality of cervical cancer
in 2018: A worldwide analysis. The Lancet Global Health 8(2): e191-e203.
Bijnsdorp, I.V., Giovannetti, E. & Peters, G.J. 2011. Analysis of drug
interactions. In Cancer Cell Culture: Methods and Protocols, edited by
Cree, I.A. New Jersey: Humana Press. pp. 421-434.
Blagosklonny, M.V. 2005. Overcoming limitations of natural anticancer
drugs by combining with artificial agents. Trends in Pharmacological
Sciences 26(2): 77-81.
Bong, F.J., Chear, N.J.Y., Ramanathan, S., Mohana-Kumaran, N.,
Subramaniam, S. & Chew, B.L. 2021. The development of callus and cell
suspension cultures of Sabah Snake Grass (Clinacanthus nutans) for the
production of flavonoids and phenolics. Biocatalysis and Agricultural
Biotechnology 33: 101977.
Castanheira, C.P., Sallas, M.L., Nunes, R.A.L., Lorenzi, N.P.C. &
Termini, L. 2020. Microbiome and cervical cancer. Pathobiology 88(2):
187-197.
Chen, J., Splenser, A., Guillory, B., Luo, J., Mendiratta, M., Belinova,
B., Halder, T., Zhang, G., Li, Y. & Garcia, J.M. 2015. Ghrelin prevents
tumour- and cisplatin-induced muscle wasting: Characterization of multiple
mechanisms involved. J. Cachexia Sarcopenia Muscle 6(2): 132-143.
Chou, T.C. 2006. Theoretical basis, experimental design, and computerized
simulation of synergism and antagonism in drug combination studies. Pharmacological
Reviews 58(3): 621-681.
Cunha, B.N., Luna-Dulcey, L., Plutin, A.M., Silveira, R.G., De Oliveira,
T.D., Cominetti, M.R., Castellano, E.E. & Batista, A.A. 2020. Selective
coordination mode of acylthiourea ligands in half-sandwich Ru(II) complexes and
their cytotoxic evaluation. Inorganic Chemistry 59(7): 5072-5085.
de Martel, C., Georges, D., Bray, F., Ferlay, J. & Clifford, G.M.
2020. Global burden of cancer attributable to infections in 2018: A worldwide
incidence analysis. The Lancet Global Health 8(2): e180-e190.
Ferlay, J., Ervik, M., Lam, F., Colombet, M., Mery, L., Piñeros, M.,
Znaor, A., Soerjomataram, I. & Bray, F. 2020. Global cancer observatory. Cancer
Today. https://gco.iarc.fr/today Accessed on 16 Jun 2023.
Franken, N.A.P., Rodermond, H.M., Stap, J., Haveman, J. & van Bree, C.
2006. Clonogenic assay of cells in vitro. Nature Protocols 1(5):
2315-2319.
Gao, Q., Feng, J., Liu, W., Wen, C., Wu, Y., Liao, Q. & Zou, L. 2022.
Opportunities and challenges for co-delivery nanomedicines based on combination
of phytochemicals with chemotherapeutic drugs in cancer treatment. Advanced
Drug Delivery Reviews 188(2025): 114445.
Ge, X., Chen, S., Liu, X., Wang, Q., Gao, L., Zhao, C., Zhang, L., Shao,
M., Yuan, X., Tian, L. & Liu, Z. 2019. Ferrocene-appended iridium (III)
complexes: Configuration regulation, anticancer application, and mechanism
research. Inorganic Chemistry 58(20): 14175-14184.
Ghosh, S. 2019. Cisplatin: The first metal based anticancer drug. Bioorganic
Chemistry 88: 102925.
Güvenç Paltun, B., Kaski, S. & Mamitsuka, H. 2021. Machine learning
approaches for drug combination therapies. Briefings in Bioinformatics 22(6): bbab293.
Han, X., Chang, W. & Xia, X. 2022. Immune checkpoint inhibitors in
advanced and recurrent/metastatic cervical cancer. Frontiers in Oncology 12: 996495.
Himiniuc, L.M., Toma, B.F., Popovici, R., Grigore, A.M., Hamod, A.,
Volovat, C., Volovat, S., Nica, I., Vasincu, D., Agop, M., Tirnovanu, M.,
Ochiuz, L., Negura, A. & Grigore, M. 2022. Update on the use of
nanocarriers and drug delivery systems and future directions in cervical
cancer. Journal of Immunology Research 2022: 1636908.
Huang, T., Wu, T., Guo, Y., Li, T. & Chan, Y. 2019. The concurrent
treatment of Scutellaria baicalensis Georgi enhances the therapeutic e
ffi cacy of cisplatin but also attenuates chemotherapy-induced cachexia and
acute kidney injury. Journal of Ethnopharmacology 243: 112075.
Kaliterna, V., Kaliterna, P., Pejkovic, L., Vulic, R., Zanchi, L. &
Cerskov, K. 2023. Prevalence of Human Papillomavirus (HPV) among females in the
general population of the split and dalmatia county and its association with
genital microbiota and infections: A prospective study. Viruses 15(2):
443.
Keene, M.R., Heslop, I.M., Sabesan, S.S. & Glass, B.D. 2019.
Complementary therapies in clinical practice complementary and alternative
medicine use in cancer: A systematic review. Complementary Therapies in
Clinical Practice 35: 33-47.
Kumar, N., Gupta, S., Yadav, T.C., Pruthi, V., Varadwaj, K. & Goel, N.
2019. Extrapolation of phenolic compounds as multi- target agents against
cancer and inflammation. Journal of Biomolecular Structure and Dynamics 37(9): 2355-2369.
Li, X., Mukandavire, C., Cucunubá, Z.M., Echeverria Londono, S., Abbas,
K., Clapham, H.E., Jit, M., Johnson, H.L., Papadopoulos, T., Vynnycky, E.,
Brisson, M., Carter, E.D., Clark, A., de Villiers, M.J., Eilertson, K.,
Ferrari, M.J., Gamkrelidze, I., Gaythorpe, K.A.M., Grassly, N.C., Hallett,
T.B., Hinsley, W., Jackson, M.L., Jean, K., Karachaliou, A., Klepac, P.,
Lessler, J., Li, X., Moore, S.M., Nayagam, S., Nguyen, D.M., Razavi, H.,
Razavi-Shearer, D., Resch, S., Sanderson, C., Sweet, S., Sy, S., Tam, Y.,
Tanvir, H., Tran, Q.M., Trotter, C.L., Truelove, S., van Zandvoort, K., Verguet,
S., Walker, N., Winter, A., Woodruff, K., Ferguson, N.M. & Garske, T. 2021.
Estimating the health impact of vaccination against ten pathogens in 98
low-income and middle-income countries from 2000 to 2030: A modelling study. The
Lancet 397(10272): 398-408.
Lin, S., Gao, K., Gu, S., You, L., Qian, S., Tang, M., Wang, J., Chen, K.
& Jin, M. 2021. Worldwide trends in cervical cancer incidence and
mortality, with predictions for the next 15 years. Cancer 127(21):
4030-4039.
Ma, L., Zhang, M., Zhao, R., Wang, D., Ma, Y. & Ai, L. 2021. Plant
natural products: Promising resources for cancer chemoprevention. Molecules 26(4): 933.
Miller, D., Morris, C.P., Maleki, Z., White, M. & Rodriguez, E.F.
2020. Health disparities in cervical cancer: Prevalence of high-risk HPV and
cytologic diagnoses according to race. Cancer Cytopathology 128(11):
860-869.
Ministry of Health Malaysia. 2020. Health Indicators 2020. Health
Informatic Center, Planning Division, Ministry of Health Malaysia.
Muhamad, N.A., Buang, S.N., Jaafar, S., Jais, R., Tan, P.S., Mustapha, N.,
Lodz, N.A., Aris, T., Sulaiman, L.H. & Murad, S. 2018. Achieving high
uptake of human papillomavirus vaccination in Malaysia through school-based
vaccination programme. BMC Public Health 18: 1402.
Nguyen, V.T., Winterman, S., Playe, M., Benbara, A., Zelek, L.,
Pamoukdjian, F. & Bousquet, G. 2022. Dose-intense cisplatin-based
neoadjuvant chemotherapy increases survival in advanced cervical cancer: An
up-to-date meta-analysis. Cancers 14(3): 842.
Núñez, J.G., Pinheiro, S., Silveira, G.F., Buffon, A. & Bruno, A.N.
2018. Antineoplastic potential of the aqueous crude extract of Eugenia
uniflora L. in human cervical cancer. Brazilian Journal of
Pharmaceutical Sciences 54(2). https://doi.org/10.1590/s2175-97902018000217267
Okunade, K.S. 2020. Human papillomavirus and cervical cancer. Journal
of Obstetrics and Gynaecology 40(5): 602-608.
Paboriboune, P., Phongsavan, K., Arounlangsy, P., Flaissier, B.,
Aphayarath, O., Phimmasone, P., Banchongphanith, K., Xayaovong, M., Jourdain,
G., Schott, A.M., Saadatian-Elahi, M., Magaud, L., Klich, A., Ngo-Giang-Huong,
N., Heard, I., Rabilloud, M., Picot, V.S. & Longuet, C. 2022. Efficacy of
careHPVTM human papillomavirus screening versus conventional
cytology tests for the detection of precancerous and cancerous cervical lesions
among women living with HIV-1 in Lao People’s Democratic Republic. Cancer
Medicine 11(9): 1984-1994.
PDQ® Adult Treatment Editorial Board. 2023. Cervical Cancer Treatment
(PDQ®). Bethesda, MD: National Cancer Institute: United States.
Purena, R., Seth, R. & Bhatt, R. 2018. Protective role of Emblica
officinalis hydro-ethanolic leaf extract in cisplatin induced
nephrotoxicity in rats. Toxicology Reports 5: 270-277.
Rocha, C.R.R., Silva, M.M., Quinet, A., Cabral-Neto, J.B. & Menck,
C.F.M. 2018. DNA repair pathways and cisplatin resistance: An intimate
relationship. Clinics 73(Supp. 1): e478s.
Roden, R.B.S. & Stern, P.L. 2018. Opportunities and challenges for
human papillomavirus vaccination in cancer. Nature Reviews Cancer 18(4):
240-254.
Saputra, E.C., Huang, L., Chen, Y. & Tucker-Kellogg, L. 2018.
Combination therapy and the evolution of resistance: The theoretical merits of
synergism and antagonism in cancer. Cancer Research 78(9): 2419-2431.
Seng, L.M., Rosman, A.N., Khan, A., Haris, N.M., Mustapha, N.A.S.,
Husaini, N.S.M. & Zahari, N.F. 2018. Awareness of cervical cancer among
women in Malaysia. International Journal of Health Sciences 12(4):
42-48.
Stelzle, D., Tanaka, L.F., Lee, K.K., Khalil, A.I., Baussano, I., Shah,
A.S.V., Mcallister, D.A., Gottlieb, S.L., Klug, S.J., Winkler, A.S., Bray, F.,
Baggaley, R., Clifford, G.M., Broutet, N. & Dalal, S. 2021. Articles
estimates of the global burden of cervical cancer associated with HIV. The
Lancet Global Health 9(2): e161-e169.
Tan, L.T.H., Khaw, K., Ong, Y.S., Khan, T.M., Lee, L.H., Lee, L.W. &
Goh, B.H. 2020. An overview of Clinacanthus nutans (Burm. f.) Lindau as
a medicinal plant with diverse pharmacological values. Plant-derived
Bioactives: Production, Properties and Therapeutic Applications. Singapore:
Springer. pp. 461-491.
Twilley, D., Rademan, S. & Lall, N. 2020. A review on traditionally
used South African medicinal plants, their secondary metabolites and their
potential development into anticancer agents. Journal of Ethnopharmacology 261: 113101.
World Health Organization (WHO). 2020. Human Papillomavirus (HPV) and
Cervical Cancer. https://www.who.int/news-room/fact-sheets/detail/cervical-cancer
(Accessed on 29 May 2023).
World Health Organization (WHO). 2021. Immunization coverage.
https://www.who.int/news-room/fact-sheets/detail/immunization-coverage
(Accessed on 5 May 2023).
Wu, J., Li, Y., He, Q. & Yang, X. 2023. Exploration of the use of
natural compounds in combination with chemotherapy drugs for tumor treatment. Molecules 28(3): 1022.
Zainuddin, N.A.S.N., Hassan, N.F.N., Zakaria, Y., Muhammad, H. &
Othman, N.H. 2019. Semi-purified fraction of Clinacanthus nutans induced
apoptosis in human cervical cancer, SiHa cells via up-regulation of Bax and
down-regulation of Bcl-2. Sains Malaysiana 48(9): 1997-2006.
Zainuddin, N.A.S.N., Muhammad, H., Nik Hassan, N.F., Othman, N.H. & Zakaria,
Y. 2020. Clinacanthus nutans standardized fraction arrested SiHa cells
at G1/S and induced apoptosis via upregulation of p53. Journal of Pharmacy
and Bioallied Sciences 12(Suppl 2): S768-S776.
Zakaria, Y. & Abdullah, H. 2018. Cytotoxicity of Clinacanthus
nutans and mechanism of action of its active fraction towards human
cervical cancer cell line, HeLA. Malaysian Journal of Health Sciences 16(2): 39-50.
*Pengarang untuk surat-menyurat; email: yusmazura@usm.my
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