In vitro experiments, LC-MS profiling, and in silico studies reveal anti-hepatocellular carcinoma properties of Canna indica L.

Subject Areas : Pharmacognosy

Rohit Kumar Dutta ¹ , Saparja Saha ² , Santanu Paul ³

1 - Laboratory of Cell and Molecular Biology, Department of Botany; Centre of Advanced Study, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, India
2 - Laboratory of Cell and Molecular Biology, Department of Botany; Centre of Advanced Study, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, India
3 - Laboratory of Cell and Molecular Biology, Department of Botany; Centre of Advanced Study, University of Calcutta, 35, Ballygunge Circular Road, Kolkata 700019, India

Received: 2024-06-17 Accepted : 2024-09-26 Published : 2024-09-29

Keywords: Canna indica, Hepatocellular carcinoma, Hep G2, In-silico, LC-MS, Liver cancer, Metabolomic profiling,

Abstract :

Hepatocellular carcinoma is one of the leading causes of cancer-related deaths worldwide, highlighting the urgent need for early detection and effective treatment. Consequently, there is a pressing demand to develop alternative drugs from natural sources. In our study, we investigated the rhizome of Canna indica as a potential resource for drug development. We assessed the anti-proliferative efficacy of the methanolic extract of the rhizome against Hep G2 liver cancer cell lines and normal cells. Our observations indicated that the extract exhibited specific anti-proliferative effects against the liver cancer cells. These results prompted us to conduct LC-MS-based metabolomic profiling of the extract, which revealed a predominance of alkaloids and phenolic compounds. Furthermore, in silico docking studies demonstrated that cadabicine methyl ether, mahanimbinol, ganoderic acid F, and cassythine exhibited strong binding affinities with key proteins involved in hepatocellular carcinoma. Therefore, we conclude that the rhizome of Canna indica is a promising source for the development of liver cancer therapeutics.

References:

Alexia, C., Fallot, G., Lasfer, M., Schweizer-Groyer, G., Groyer, A., 2004. An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocarcinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis. Biochem. Pharmacol. 68(6), 1003-1015.
Al-Snafi, A.E., 2015. Bioactive components and pharmacological effects of Canna indica-An overview. Int. J. Pharmacol. Toxicol. 5(2), 71-75.
Azmi, A.S., Bhat, S.H., Hanif, S., Hadi, S.M., 2006. Plant polyphenols mobilize endogenous copper in human peripheral lymphocytes leading to oxidative DNA breakage: A putative mechanism for anticancer properties. FEBS. Lett. 580(2), 533-538.
Banerjee, P., Eckert, A.O., Schrey, A.K., Preissner, R., 2018. ProTox-II: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Res. 46(W1), W257-W263.
Berretta, M., Rinaldi, L., Di Benedetto, F., Lleshi, A., De Re, V., Facchini, G., De Paoli, P., Di Francia, R., 2016. Angiogenesis inhibitors for the treatment of hepatocellular carcinoma. Front. Pharmacol. 7, 428.
Bhavana, K., Chellappa, V., Souradeep, D., Biswajit, D., Prasad, N.R.V., 2023. The incidence and severity of patient-reported side effects of chemotherapy in routine clinical care: A prospective observational study. Cureus 15(4).
Cao, J., Xia, X., Chen, X., Xiao, J., Wang, Q., 2013. Characterization of flavonoids from Dryopteris erythrosora and evaluation of their antioxidant, anticancer and acetylcholinesterase inhibition activities. Food Chem. Toxicol. 51, 242-250.
Chigurupati, S., Alharbi, N.A.R., Sharma, A.K., Alhowail, A., Vardharajula, V.R., Vijayabalan, S., Das, S., Kauser, F., Amin, E., 2021. Pharmacological and pharmacognostical valuation of Canna indica leaves extract by quantifying safety profile and neuroprotective potential. Saudi J. Biol. Sci. 28(10), 5579-5584.
Daina, A., Michielin, O., Zoete, V., 2017. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep. 7(1), 42717.
Dekdouk, N., Ameddah, S., Bensouici, C., Ibtissem, M., Ahmed, M., Martel, F., 2024. Antioxidant properties and anticancer activity of Olea europaea L. olive and Ficus carica fruit extracts against pancreatic cancer cell lines. Trends Phytochem. Res. 8(2), 80-92.
Dimri, M., Satyanarayana, A., 2020. Molecular signaling pathways and therapeutic targets in hepatocellular carcinoma. Cancers (Basel) 12(2), 491.
Durán-Iturbide, N.A., Díaz-Eufracio, B.I., Medina-Franco, J.L., 2020. In silico ADME/Tox profiling of natural products: A focus on BIOFACQUIM. ACS Omega 5(26), 16076-16084.
Flores-Holguín, N., Frau, J., Glossman-Mitnik, D., 2021. In silico pharmacokinetics, ADMET study and conceptual DFT analysis of two plant cyclopeptides isolated from rosaceae as a computational peptidology approach. Front. Chem. 9, 708364.
Giordano, S., Columbano, A., 2014. Met as a therapeutic target in HCC: Facts and hopes. J. Hepatol. 60(2), 442-452.
Gupta, S.C., Tyagi, A.K., Deshmukh-Taskar, P., Hinojosa, M., Prasad, S., Aggarwal, B.B., 2014. Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols. Arch. Biochem. Biophys. 559, 91-99.
Hatanaka, T., Naganuma, A., Kakizaki, S., 2021. Lenvatinib for hepatocellular carcinoma: A literature review. Pharmaceuticals 14(1), 36.
Huang, P., Xu, X., Wang, L., Zhu, B., Wang, X., Xia, J., 2014. The role of EGF‐EGFR signalling pathway in hepatocellular carcinoma inflammatory microenvironment. J. Cell. Mol. Med. 18(2), 218-230.
Huang, S.P., Shieh, G.J., Ko, J.L., Weng, Z.Y., Lin, J.G., Chen, J.C., 2009. Inhibition of subgenomic hepatitis C virus RNA transcription by Chinese herbal extracts. Pharm. Biol. 47(2), 111-119.
Iqbal, J., Abbasi, B.A., Mahmood, T., Kanwal, S., Ali, B., Shah, S.A., Khalil, A.T., 2017. Plant-derived anticancer agents: A green anticancer approach. Asian Pac. J. Trop. Biomed. 7(12), 1129-1150.
Jeyaraman, V., Muthukkumarasamy, S., Antony, J.V.A., 2011. Phytochemical analysis of Canna indica L. IJONS 1(5), 285-90.
Kanase, V.A.N.I.T.A., Vishwakarma, S.U.N.I.T.A., 2018. Treatment of various diseases by Canna indica L.-A promising herb. Asian J. Pharm. Clin. Res. 11(12), 51-56.
Kim, S., Thiessen, P.A., Bolton, E.E., Chen, J., Fu, G., Gindulyte, A., Han, L., He, J., He, S., Shoemaker, B.A., Wang, J., 2016. PubChem substance and compound databases. Nucleic Acids Res. 44(D1), D1202-D1213.
Kiran, A., Altaf, A., Sarwar, M., Malik, A., Maqbool, T., Ali, Q., 2023. Phytochemical profiling and cytotoxic potential of Arnebia nobilis root extracts against hepatocellular carcinoma using in-vitro and in-silico approaches. Sci. Rep. 13(1), 11376.
Malíková, J., Swaczynová, J., Kolář, Z., Strnad, M., 2008. Anticancer and antiproliferative activity of natural brassinosteroids. Phytochemistry 69(2), 418-426.
Maroun, C.R. and Rowlands, T., 2014. The Met receptor tyrosine kinase: A key player in oncogenesis and drug resistance. Pharmacol. Ther. 142(3), 316-338.
Mohadjerani, M., Asadollahi, S., 2019. Veronica crista-galli Steven and Veronica persica Poir. as anticancer and antioxidant plants in-vitro. Trends Phytochem. Res. 3(1), 61-66.
Nataru, S., Pulicherla, Y., Gaddala, B., 2014. A review on medicinal plants as a potential source for cancer. Int. J. Pharm. Sci. Rev. Res. 26(1), 235-48.
Odugbemi, T.O., Akinsulire, O.R., Aibinu, I.E., Fabeku, P.O., 2007. Medicinal plants useful for malaria therapy in Okeigbo, Ondo State, Southwest Nigeria. Afr. J. Tradit. Complement. Altern. Med. 4(2), 191-198.
Pang, Y., Eresen, A., Zhang, Z., Hou, Q., Wang, Y., Yaghmai, V., Zhang, Z., 2022. Adverse events of sorafenib in hepatocellular carcinoma treatment. Am. J. Cancer Res. (6), 2770.
Parida, P.K., Mahata, B., Santra, A., Chakraborty, S., Ghosh, Z., Raha, S., Misra, A.K., Biswas, K., Jana, K., 2018. Inhibition of cancer progression by a novel trans-stilbene derivative through disruption of microtubule dynamics, driving G2/M arrest, and p53-dependent apoptosis. CDD 9(5), 448.
Pires, D.E., Blundell, T.L., Ascher, D.B., 2015. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J. Med. Chem. 58(9), 4066-4072.
Prasanth, D.S.N.B.K., Murahari, M., Chandramohan, V., Bhavya, G., Lakshmana Rao, A., Panda, S.P., Rao, G.K., Chakravarthi, G., Teja, N., Suguna Rani, P., Ashu, G., 2021. In-silico strategies of some selected phytoconstituents from Melissa officinalis as SARS CoV-2 main protease and spike protein (COVID-19) inhibitors. Mol. Simul. 47(6), 457-470.
Raja, A., Park, I., Haq, F., Ahn, S.M., 2019. FGF19-FGFR4 signaling in hepatocellular carcinoma. Cells 8(6), 536.
Rajpal, S., Kumar, A., Joe, W., 2018. Economic burden of cancer in India: Evidence from cross-sectional nationally representative household survey, 2014. PloS One 13(2), e0193320.
Ray, R., Saha, S., Paul, S., 2022. Two novel compounds, ergosterol and ergosta-5,8-dien-3-ol, from Termitomyces heimii Natarajan demonstrate promising anti-hepatocarcinoma activity. J. Tradit. Chin. Med. Sci. 9(4), 443-453.
Robinson, B., Dutcus, C., Gianoukakis, A., Haddad, R., Schlumberger, M., Shah, M.H., Sherman, E., Sherman, S.I., Teng, A., Wirth, L., 2017. Incidence and timing of common adverse events in Lenvatinib-treated patients from the SELECT trial and their association with survival outcomes. Endocrine 56(1),121-128.
Rumgay, H., Arnold, M., Ferlay, J., Lesi, O., Cabasag, C.J., Vignat, J., Laversanne, M., McGlynn, K.A., Soerjomataram, I., 2022. Global burden of primary liver cancer in 2020 and predictions to 2040. J. Hepatol. 77(6), 1598-1606.
Sarje, S.K., Ingole, K., Angad, S., Priya, B., Ghiware, N.B., 2019. A pharmacognostic and pharmacological review on Canna indica Linn. Int. J. Res. Pharm. Pharm. Sci. 9(3), 61-77.
Smith, R.D., Mallath, M.K., 2019. History of the growing burden of cancer in India: From antiquity to the 21st century. J. Glob. Oncol. 5, 1-15.
Srivastava, J., Vankar, P.S., 2010. Canna indica flower: New source of anthocyanins. Int. J. Plant Physiol. Biochem. 48(12), 1015-1019.
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 Cancer J. Clin. 71(3), 209-249.
Thepouyporn, A., Yoosook, C., Chuakul, W., Thirapanmethee, K., Napaswad, C., Wiwat, C., 2012. Purification and characterization of anti-HIV-1 protein from Canna indica L. leaves. Southeast Asian J. Trop. Med. Public Health. 43(5), p.1153.
Vignesh, A., Selvakumar, S., Vasanth, K., 2022. Comparative LC-MS analysis of bioactive compounds, antioxidants and antibacterial activity from leaf and callus extracts of Saraca asoca. Phytomedicine Plus 2(1), 100167.
Wang, H., Rao, B., Lou, J., Li, J., Liu, Z., Li, A., Cui, G., Ren, Z., Yu, Z., 2020. The function of the HGF/c-Met axis in hepatocellular carcinoma. Front. Cell Dev. Biol. 8, 55.
Widyarini, S., Nugroho, L.H., Pratiwi, R., 2020. Phytochemical analysis and cytotoxic activities of two distinct cultivars of Ganyong rhizomes (Canna indica) against the WiDr colon cancer cell line. Biodiversitas 21(4).