Author(s): Awik P. D. Nurhayati, Mardi Santoso, Yuniar I. Susanti, Fitri Lianingsih, Evira N. Oktyasti, Edwin Setiawan, Nurul Jadid, Arif Luqman

Email(s): awiknurhayati@gmail.com

DOI: 10.52711/0974-360X.2025.00113   

Address: Awik P. D. Nurhayati1*, Mardi Santoso2, Yuniar I. Susanti1, Fitri Lianingsih1, Evira N. Oktyasti1, Edwin Setiawan1, Nurul Jadid1, Arif Luqman1
1Department of Biology, Faculty of Science and Data Analytics, Institut Teknologi Sepuluh Nopember, Surabaya 60111, East Java, Indonesia.
2Department of Chemistry, Faculty of Science and Data Analytics, Institut Teknologi Sepuluh Nopember, Surabaya 60111, East Java, Indonesia.
*Corresponding Author

Published In:   Volume - 18,      Issue - 2,     Year - 2025


ABSTRACT:
Cancer can arise from the malignant transformation of normal cells due to carcinogenic induction that damages DNA and disrupts the cell cycle. DNA damage is corrected in the G1 phase of the cell cycle by expression and activation of the p53 tumor suppressor. The prominent outcomes of p53 activation are cycle arrest and apoptosis. Therefore, p53 is used as a target for anticancer drug development. Hyperactivation or deregulation of the MAPK (mitogen activated protein kinase) pathway can affect liver cancer. MAPK activation plays an important role in regulating inflammation associated with cancer development. Therefore, MAPK is considered as a therapeutic target. Trisindoline 1 is a natural compound that has previously been shown to have high cytotoxic effect on HepG2 cells. This study aims to decide the potential of trisindoline 1 as an anticancer drug for HepG2 liver cancer cell line and to decide the activity of trisindoline 1 with the MAPK pathway targeting HepG2 cancer through in silico analysis. Molecular docking was performed on trisindoline 1 against ERK1, JNK2 and p38 proteins in the MAPK pathway. Pharmacokinetic and physicochemical analysis were carried out using SwissADME for evaluation of drug-likeness. Cell proliferation was analysed using the MTT assay method. Trisindoline 1 showed high cytotoxic activity against HepG2 with an IC50 value of 2.837 µg/ml and showed low toxicity against Vero cells. Based on the analysis of physicochemical properties, trisindoline 1 met the properties of drug-likeness and has lower toxicity compared to Doxorubicin. The docking results show that trisindoline 1 has the potential to be an inhibitor of the ERK2, JNK1 and p38 MAPK pathways. These results suggest that trisindoline 1 has the potential as an anticancer drug.


Cite this article:
Awik P. D. Nurhayati, Mardi Santoso, Yuniar I. Susanti, Fitri Lianingsih, Evira N. Oktyasti, Edwin Setiawan, Nurul Jadid, Arif Luqman. The Potency Anticancer Candidate of Trisindolina 1 with In vitro and In Silico Methods. Research Journal of Pharmacy and Technology.2025;18(2):765-2. doi: 10.52711/0974-360X.2025.00113

Cite(Electronic):
Awik P. D. Nurhayati, Mardi Santoso, Yuniar I. Susanti, Fitri Lianingsih, Evira N. Oktyasti, Edwin Setiawan, Nurul Jadid, Arif Luqman. The Potency Anticancer Candidate of Trisindolina 1 with In vitro and In Silico Methods. Research Journal of Pharmacy and Technology.2025;18(2):765-2. doi: 10.52711/0974-360X.2025.00113   Available on: https://rjptonline.org/AbstractView.aspx?PID=2025-18-2-45


REFERENCES:
1.    Elkhateeb WA. Waill A. Elkhateeb. Mohamed A. Mohamed. Walid F. Mahmoud E. Ibrahim M. Nafady. Ghoson M. Daba. Molecular Identification, Metabolites profiling, Anti-breast cancer, Anti-colorectal cancer, and antioxidant potentials of Streptomyces zaomyceticus AA1 isolated from a remote bat cave in Egypt. Research Journal of Pharmacy and Technology. 2020; 13(6): 3072-3080. doi:10.5958/0974-360X.2020.00545.4
2.    Vidhya RU. Prabhu M. Bhuminathan S. Review on anticancer properties of piperine in oral cancer: Therapeutic perspectives. Research Journal of Pharmacy and Technology. 2022; 15(7): 3338-3342. doi:10.52711/0974-360X.2022.00558
3.    Crissien A. M. Frenette C. Current management of hepatocellular carcinoma. World Journal Gastroenterol. 2014; 20(30). doi:10.3748/wjg.v20.i30.10223
4.    Kumar S. Mohammad, H. Vora H. Kar K. Reporting Quality of Randomized Controlled Trials of Periodontal Diseases in Journal Abstracts-A Cross-sectional Survey and Bibliometric Analysis. Journal of Evidence-Based Dental Practice. 2018; 18(2): 130-141. doi:10.1016/j.jebdp.2017.08.005
5.    Taylor CA. Zheng Q. Liu Z. Thompson JE. Role of p38 and JNK MAPK signaling pathways and tumor suppressor p53 on induction of apoptosis in response to Ad-eIF5A1 in A549 lung cancer cells. Molecular Cancer. 2013; 12(1). doi:10.1186/1476-4598-12-35
6.    Muthuraj M. Palabhanvi B. Misra S. Kumar V. Sivalingavasu K. Das D. Flux balance analysis of Chlorella sp. FC2 IITG under photoautotrophic and heterotrophic growth conditions. Photosynthesis Research. 2013; 118(1-2): 167-179. doi:10.1007/s11120-013-9943-x
7.    Chen VY. Posada MM. Zhao L. Rosania GR. Rapid doxorubicin efflux from the nucleus of drug-resistant cancer cells following extracellular drug clearance. Pharmaceutical Research. 2007; 24(11): 2156-2167. doi:10.1007/s11095-007-9369-2
8.    Sakaue-Sawano A. Yo M. Komatsu N. et al. Genetically Encoded Tools for Optical Dissection of the Mammalian Cell Cycle. Molecular Cell. 2017; 68(3): 626-640. doi:10.1016/j.molcel.2017.10.001
9.    Al Bitar S. Gali-Muhtasib H. The role of the cyclin dependent kinase inhibitor p21cip1/waf1 in targeting cancer: Molecular mechanisms and novel therapeutics. Cancers (Basel). 2019; 11(10). doi:10.3390/cancers11101475
10.    Barr AR. Cooper S. Heldt FS. et al. DNA damage during S-phase mediates the proliferation-quiescence decision in the subsequent G1 via p21 expression. Nature Communications. 2017; 8. doi:10.1038/ncomms14728
11.    Zhang K. Tu M. Gao W. et al. Hollow Prussian Blue Nanozymes Drive Neuroprotection against Ischemic Stroke via Attenuating Oxidative Stress, Counteracting Inflammation, and Suppressing Cell Apoptosis. Nano Letters. 2019; 19(5): 2812-2823. doi:10.1021/acs.nanolett.8b04729
12.    Lee JH. Kim KT. Regulation of cyclin-dependent kinase 5 and p53 by ERK1/2 pathway in the DNA damage-induced neuronal death. J Cell Physiol. 2007; 210(3): 784-797. doi:10.1002/jcp.20899
13.    Gen SW. The functional interactions between the p53 and MAPK signaling pathways. Cancer Biol Ther. 2004; 3(2): 156-161. doi:10.4161/cbt.3.2.614
14.    Kobayashi M. Aoki S. Gato K. Matsunami K. Kurosu M. Kitagawa I. Marine Natural Products. XXXIV. Trisindoline, a New Antibiotic Indole Trimer, Produced by a Bacterium of Vibrio sp. Separated from the Marine Sponge Hyrtios altum. Chem Pharm Bull (Tokyo). 1994; 42(12): 2449-2451. doi:10.1248/cpb.42.2449
15.    Rahayu WP. Achmad A. Ekowati H. Antiproliferative Activity of Black Seed (Nigella sativa) on 7,12-dimethylbenz-[a]antracene (DMBA) Induced Mice Lung Cell. Makara Journal of Health Research. 2013; 16(2): 51-56. doi:10.7454/msk.v16i2.1629
16.    Kalita S. Kumar G. Karthik L. Rao KVB. A review on medicinal properties of lantana camara linn. Research Journal of Pharmacy and Technology. 2012; 5(6): 711-715.
17.    Mohanasundaram S. Rangarajan N. Sampath V. Porkodi K. Dass Prakash MV. Monicka N. Gc-ms identification of anti-inflammatory and anticancer metabolites in edible milky white mushroom (Calocybe indica) against human breast cancer (mcf-7) cells. Research Journal of Pharmacy and Technology. 2021; 14(8): 4300-4306. doi:10.52711/0974-360X.2021.00747
18.    Mayavanshi A. Gajjar S. Floating drug delivery systems to increase gastric retention of drugs: A Review. Research Journal of Pharmacy and Technology. 2008; 1(4): 345-348.
19.    Karali N. Terzioǧlu N. Gürsoy A. Synthesis and primary cytotoxicity evaluation of new 5-bromo-3-substituted-hydrazono-1H-2-indolinones. Archiv der Pharmazie. 2002; 335(8): 374-380. doi:10.1002/1521-4184(200211)335:8<374::AID-ARDP374>3.0.CO;2-K
20.    AbuHammad S. Zihlif M. Gene expression alterations in doxorubicin resistant MCF7 breast cancer cell line. Genomics. 2013; 101(4): 213-220. doi:10.1016/j.ygeno.2012.11.009
21.    Alam F. Badruddeen. Kharya AK. Juber A. Khan MI. Naringin: Sources, chemistry, toxicity, pharmacokinetics, pharmacological evidences, molecular docking and cell line study. Research Journal of Pharmacy and Technology. 2020; 13(5): 2507-2515. doi:10.5958/0974-360X.2020.00447.3
22.    Zhou J. Liu M. Aneja R. Chandra R. Lage H. Joshi HC. Reversal of P-glycoprotein-mediated multidrug resistance in cancer cells by the c-Jun NH2-terminal kinase. Cancer Research. 2006; 66(1): 445-452. doi:10.1158/0008-5472.CAN-05-1779
23.    Iwamaru A, Iwado E, Kondo S, et al. Eupalmerin acetate, a novel anticancer agent from Carribean gorgonian octocorals, induces apoptosis in malignat glioma cells via the c-Jun NH2-terminal kinase pathway. Molecular Cancer Therapeutics. 2007; 6(1): 184-192. doi:10.1158/1535-7163.MCT-06-0422
24.    Kodical DD. James JP. Deepthi K. Kumar P. Cyriac C. Gopika K V. Admet, molecular docking studies and binding energy calculations of pyrimidine-2-thiol derivatives as cox inhibitors. Research Journal of Pharmacy and Technology. 2020; 13(9): 4200-4206. doi:10.5958/0974-360X.2020.00742.8
25.    Proboningrat A, Kharisma VD, Ansori ANM, et al. In silico Study of Natural inhibitors for Human papillomavirus-18 E6 protein. Research Journal of Pharmacy and Technology. 2022; 15(3): 1251-1256. doi:10.52711/0974-360X.2022.00209
26.    Parameswari P. Devika R. In silico molecular docking studies of quercetin compound against anti-inflammatory and anticancer proteins. Research Journal of Pharmacy and Technology. 2019; 12(11): 5305-5309. doi:10.5958/0974-360X.2019.00919.3
27.    Marcou G. Rognan D. Optimizing fragment and scaffold docking by use of molecular interaction fingerprints. Journal of Chemical Information and Modeling. 2007; 47(1): 195-207. doi:10.1021/ci600342e
28.    Dushimemaria F. Du Preez CI. Mumbengegwi DR. Randomized anticancer and cytotoxicity activities of Guibourtia coleosperma and Diospyros chamaethamnus. African Journal of Traditional, Complementary and Alternative Medicines. 2017; 14(4). doi:10.21010/ajtcam.v14i4.1
29.    Roemeling S. Roobol MJ. de Vries SH. et al. Active Surveillance for Prostate Cancers Detected in Three Subsequent Rounds of a Screening Trial: Characteristics, PSA Doubling Times, and Outcome. European Urology. 2007; 51(5): 1244-1250. doi:10.1016/j.eururo.2006.11.053
30.    Nurhayati APD. Rihandoko A. Fadlan A. Ghaissani SS. Jadid N. Setiawan E. Anti-cancer potency by induced apoptosis by molecular docking P53, caspase, cyclin D1, cytotoxicity analysis and phagocytosis activity of trisindoline 1,3 and 4. Saudi Pharmaceutical Journal. 2022; 30(9): 1345-1359. doi:10.1016/j.jsps.2022.06.012
31.    Kirk GD. Camus-Randon AM. Mendy M. et al. Ser-249 p53 mutations in plasma DNA of patients with hepatocellular carcinoma from The Gambia. Journal of the National Cancer Institute. 2000; 92(2): 148-153. doi:10.1093/jnci/92.2.148
32.    Novitasari D. Jenie RI. Wulandari F. et al. Curcumin-like structure (Cca-1.1) induces permanent mitotic arrest (senescence) on triple-negative breast cancer (tnbc) cells, 4t1. Research Journal of Pharmacy and Technology. 2021; 14(8): 4375-4382. doi:10.52711/0974-360X.2021.00760
33.    Prasojo SL. Hartanto FAD. Yuniarti N. Ikawati Z. Istyastono EP. Docking of 1-phenylsulfonamide-3-trifluoromethyl-5-parabromophenyl-pyrazole to cyclooxygenase-2 using plants. Indonesian Journal of Chemistry. 2010; 10(3): 348-351. doi:10.22146/ijc.21441
34.    Tian W. Chen C. Lei X. Zhao J. Liang J. CASTp 3.0: Computed atlas of surface topography of proteins. Nucleic Acids Res. 2018; 46(W1). doi:10.1093/nar/gky473
35.    Qiu L. Liu M. Pan K. A triple staining method for accurate cell cycle analysis using multiparameter flow cytometry. Molecules. 2013; 18(12): 15412-15421. doi:10.3390/molecules181215412
36.    Pandey R. Heidmann S. Lehner CF. Epithelial re-organization and dynamics of progression through mitosis in Drosophila separase complex mutants. Journal of Cell Science. 2005; 118(4): 733-742. doi:10.1242/jcs.01663
37.    Politaev VV. Petrenko AA. Nalbandyan VB. Medvedev BS. Shvetsova ES. Crystal structure, phase relations and electrochemical properties of monoclinic Li2MnSiO4. Journal of Solid State Chemistry. 2007; 180(3): 1045-1050. doi:10.1016/j.jssc.2007.01.001
38.    Brundha MP. Pathmashri VP. Sundari S. Quantitative changes of red blood cells in cancer patients under palliative radiotherapy-a retrospective study. Research Journal of Pharmacy and Technology. 2019; 12(2): 687-692. doi:10.5958/0974-360X.2019.00122.7
39.    Lüpertz R. Wätjen W. Kahl R. Chovolou Y. Dose- and time-dependent effects of doxorubicin on cytotoxicity, cell cycle and apoptotic cell death in human colon cancer cells. Toxicology. 2010; 271(3): 115-121. doi:10.1016/j.tox.2010.03.012
40.    Mustikasari K. Ariyani D. Skrining fitokimia ekstrak metanol biji Kalangkala (Litsea angulata). Jurnal Berkala Ilmiah Sains dan Terapan Kimia. 2010; 4: 131-136.
41.    Nepali K. Lee HY. Liou JP. Nitro-Group-Containing Drugs. Journal of Medicinal Chemistry. 2019; 62(6): 2851-2893. doi:10.1021/acs.jmedchem.8b00147
42.    Muthu Mohamed J. Ahmad F. Kishore N. Al-Subaie AM. Soluble 1:1 Stoichiometry curcumin binary complex for potential apoptosis in human colorectal adenocarcinoma cells (SW480 and Caco-2 cells). Research Journal of Pharmacy and Technology. 2021; 14(1): 129-135. doi:10.5958/0974-360X.2021.00023.8
43.    Pistritto G. Trisciuoglio D. Ceci C. Alessia G. D’Orazi G. Apoptosis as anticancer mechanism: Function and dysfunction of its modulators and targeted therapeutic strategies. Aging. 2016; 8(4): 603-619. doi:10.18632/aging.100934


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