In silico assessment of the anticancer effects of tecomaquinone I, brevilin A, erybraedin A, evodiamine, and sumadain C in oral squamous cell carcinoma

Abstract

Oral squamous cell carcinoma (OSCC) is one of the most common malignancies globally. Current treatment modalities, including chemotherapy and radiotherapy, often result in adverse effects that compromise the quality of life for patients. An alternate approach involves using phytocomposites as substitutes for commercial chemotherapeutic agents, potentially offering improved therapeutic outcomes with minimal adverse effects. The study aims to investigate the anticancer effects of phytocomposites in OSCC. A literature search was performed to select relevant phytocomposites for the analysis. The chosen compounds included tecomaquinone I, brevilin A, erybraedin A, evodiamine, and sumadain C. Bioactive compound information was extracted using online software tools, such as ZINC15, SwissADME, PharmaGist, and ZINCPharmer. The target protein for this study was Harvey rat sarcoma virus oncogene and its structure was obtained from the Protein Data Bank. On evaluating the binding affinities of these phytocomposites to the target protein, it was found that ZINC94088045 and ZINC94241870 exhibited the highest binding affinities, with values of -18.71 and -15.75 kcal/mol, respectively. These compounds also demonstrated favorable pharmacokinetic properties, with total polar surface area values of 85.11 Ų and 122.39 Ų, log P values of 2.59 and 1.77, and bioavailability scores of 0.55 and 0.56, respectively. Notably, these compounds also showed high gastrointestinal absorption and low cytotoxicity. The final phytocomposite combination displayed a strong binding affinity to the target protein while maintaining low cytotoxicity. This study highlights the potential anticancer effect of phytocomposites on OSCC with negligible cytotoxicity, offering a promising alternative to conventional treatments.

Keywords

Binding affinity / Oral squamous cell carcinoma / Phytocomposites / Harvey rat sarcoma virus oncogene

Funding

None.

Conflict of interest

The authors declare no potential conflicts of interest to the research, authorship, and/or publication of this article.

References

[1] Petersen PE. Strengthening the prevention of oral cancer: The WHO perspective. Community Den Oral Epidemiol. 2005; 33(6):397-399. doi: 10.1111/j.1600-0528.2005.00251.x

[2] Feller L, Lemmer J. Oral squamous cell carcinoma: Epidemiology, clinical presentation and treatment. J Cancer Ther. 2012; 03(4):263-268. doi: 10.4236/jct.2012.34037

[3] Sagar S, Ramani P. Tobacco as a trigger for oral squamous cell carcinoma arising in the background of oral submucous fibrosis: A clinicopathological study. J Popul Ther Clin Pharmacol 2023; 30(6). doi: 10.47750/jptcp.2023.30.06.012

[4] Nussbaumer S, Bonnabry P, Veuthey JL, Fleury-Souverain S. Analysis of anticancer drugs: A review. Talanta. 2011; 85(5):2265-2289. doi: 10.1016/j.talanta.2011.08.034

[5] Priyadarshini R, Ramasubramanian A, Ramani P, Doble M. Identification of novel potential herbal drug targets against beta-catenin in the treatment of oral squamous cell carcinoma. Asian Pac J Cancer Prev 2024; 25(12):4181-4188. doi: 10.31557/apjcp.2024.25.12.4181

[6] Dillard CJ, German JB. Phytochemicals: Nutraceuticals and human health. J Sci Food Agric. 2000; 80(12):1744-1756. doi: 10.1002/1097-0010(20000915)80:12<1744:AID-JSFA725> 3.0.CO;2-W

[7] Burcher JT, DeLiberto LK, Allen AM, Kilpatrick KL, Bishayee A. Bioactive phytocompounds for oral cancer prevention and treatment: A comprehensive and critical evaluation. Med Res Rev. 2023; 43(6):2025-2085. doi: 10.1002/med.21969

[8] Yadav N, Parveen S, Banerjee M. Potential of nano-phytochemicals in cervical cancer therapy. Clin Chim Acta. 2020; 505:60-72. doi: 10.1016/j.cca.2020.01.035

[9] Farrand L, Oh SW, Song YS, Tsang BK. Phytochemicals: A multitargeted approach to gynecologic cancer therapy. BioMed Res Int. 2014; 2014:890141. doi: 10.1155/2014/890141

[10] Liu J, Peng Y, Wei W. Cell cycle on the crossroad of tumorigenesis and cancer therapy. Trends Cell Biol. 2021; 32(1):30-44. doi: 10.1016/j.tcb.2021.07.001

[11] Li Z, Li D, Zhang G, et al. Methylation-associated silencing of MicroRNA-335 contributes tumor cell invasion and migration by interacting with RASA1 in gastric cancer. Am J Cancer Res. 2014; 4(6):648-662.

[12] Prior IA, Lewis PD, Mattos C. A comprehensive survey of RAS mutations in cancer. Cancer Res. 2012; 72(10):2457-2467. doi: 10.1158/0008-5472.can-11-2612

[13] Rodenhuis S, Slebos RJ, Boot AJ, et al. Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res. 1988; 48(20):5738-5741.

[14] Vogelstein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. New England J Med. 1988; 319(9):525-532. doi: 10.1056/nejm198809013190901

[15] Shibata D, Almoguera C, Forrester K, et al. Detection of c-K-ras mutations in fine needle aspirates from human pancreatic adenocarcinomas. Cancer Res. 1990; 50(4):1279-1283.

[16] Lyu H, Li M, Jiang Z, Liu Z, Wang X. Correlate the TP53 mutation and the HRAS mutation with immune signatures in head and neck squamous cell cancer. Comput Struct Biotechnol J. 2019; 17:1020-1030. doi: 10.1016/j.csbj.2019.07.009

[17] Dou R, Zhang L, Lu T, et al. Identification of a novel HRAS variant and its association with papillary thyroid carcinoma. Oncol Lett. 2018; 5(4):4511-4516. doi: 10.3892/ol.2018.7818

[18] Cha Y, Erez T, Reynolds IJ, et al. Drug repurposing from the perspective of pharmaceutical companies. Br J Pharmacol. 2017; 175(2):168-180. doi: 10.1111/bph.13798

[19] Priyadarshini G, Sukumaran G, Dilipan E, Ramani P. Targeting oral cancer: In silico docking studies of phytochemicals on oncogenic molecular markers. Asian Pac J Cancer Prev 2024; 25(6):2069-2075. doi: 10.31557/apjcp.2024.25.6.2069

[20] Cui JJ, Tran-Dubé M, Shen H, et al. Structure based drug design of Crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (C-MET) kinase and Anaplastic Lymphoma Kinase (ALK). J Med Chem. 2011; 54(18):6342-6363. doi: 10.1021/jm2007613

[21] Cui W, Aouidate A, Wang S, Yu Q, Li Y, Yuan S. Discovering anti-cancer drugs via computational methods. Front Pharmacol. 2020; 11:733. doi: 10.3389/fphar.2020.00733

[22] Prada-Gracia D, Huerta-Yépez S, Moreno-Vargas LM. Application of computational methods for anticancer drug discovery, design, and optimization. Bol Méd Hosp Infant Méx. 2016; 73(6):411-423. doi: 10.1016/j.bmhimx.2016.10.006

[23] Spinello A, Ritacco I, Magistrato A. Recent advances in computational design of potent aromatase inhibitors: Open-eye on endocrine-resistant breast cancers. Expert Opin Drug Discov. 2019; 14(10):1065-1076. doi: 10.1080/17460441.2019.1646245

[24] Ohbayashi N, Murayama K, Kato‐Murayama M, et al. Structural basis for the inhibition of cyclin G‐Associated kinase by gefitinib. ChemistryOpen. 2018; 7(9):713-719. doi: 10.1002/open.201800177

[25] Masago K, Togashi Y, Fukudo M, et al. Good clinical response to erlotinib in a non-small cell lung cancer patient harboring multiple brain metastases and a double active somatic epidermal growth factor gene mutation. Case Rep Oncol. 2010; 3(2):98-105. doi: 10.1159/000310830

[26] Xia W, Liu Z, Zong R, et al. Truncated ERBB2 expressed in tumor cell nuclei contributes to acquired therapeutic resistance to ERBB2 kinase inhibitors. Mol Cancer Ther. 2011; 10(8):1367-1374. doi: 10.1158/1535-7163.mct-10-0991

[27] Asmane I, Céraline J, Duclos B, et al. New strategies for medical management of castration-resistant prostate cancer. Oncology. 2011; 80(1-2):1-11. doi: 10.1159/000323495

[28] Roskoski R Jr. STI-571: An anticancer protein-tyrosine kinase inhibitor. Biochem Biophys Res Commun. 2003; 309(4):709-717. doi: 10.1016/j.bbrc.2003.08.055

[29] Lam B, Arikawa Y, Cramlett J, et al. Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK). Bioorg Med Chem Lett. 2016; 26(24):5947-5950. doi: 10.1016/j.bmcl.2016.10.087

[30] Wang M, Yang JCH, Mitchell PL, et al. Sunvozertinib, a selective EGFR inhibitor for previously treated non-small cell lung cancer with EGFR exon 20 insertion mutations. Cancer Discov. 2022; 12(7):1676-1689. doi: 10.1158/2159-8290.cd-21-1615

[31] Tron AE, Belmonte MA, Adam A, et al. Discovery of Mcl- 1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun. 2018; 9(1):5341. doi: 10.1038/s41467-018-07551-w

[32] Wang L, Yang C, Xie C, et al. Pharmacologic characterization of fluzoparib, a novel poly(ADP‐ribose) polymerase inhibitor undergoing clinical trials. Cancer Sci. 2019; 110(3):1064-1075. doi: 10.1111/cas.13947

[33] Sahu RK, Verma VV, Kumar A, Tandon S, Das BC, Hedau ST. In silico prediction and interaction of resveratrol on methyl-CpG binding proteins by molecular docking and MD simulations study. RSC Adv. 2022; 12(18):11493-11504. doi: 10.1039/d2ra00432a

[34] Shen LA, Peng X, Bao Y, et al. Design, synthesis and biological evaluation of quercetin derivatives as novel β-catenin/B-cell lymphoma 9 protein-protein interaction inhibitors. Eur J Med Chem. 2022; 247:115075. doi: 10.1016/j.ejmech.2022.115075

[35] Olotu FA, Agoni C, Adeniji E, Abdullahi M, Soliman ME. Probing gallate-mediated selectivity and high-affinity binding of epigallocatechin gallate: A way-forward in the design of selective inhibitors for anti-apoptotic Bcl-2 proteins. Appl Biochem Biotechnol. 2018; 187(3):1061-1080. doi: 10.1007/s12010-018-2863-7

[36] Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017; 170(1):17-33. doi: 10.1016/j.cell.2017.06.009

[37] Hancock JF. Ras proteins: Different signals from different locations. Nat Rev Mol Cell Biol. 2003; 4(5):373-385. doi: 10.1038/nrm1105

[38] Ahmadian MR, Stege P, Scheffzek K, Wittinghofer A. Confirmation of the arginine-finger hypothesis for the GAP-stimulated GTP-hydrolysis reaction of Ras. Nat Struct Biol. 1997; 4(9):686-689. doi: 10.1038/nsb0997-686

[39] Gimple RC, Wang X. RAS: Striking at the core of the oncogenic circuitry. Front Oncol. 2019; 9:965. doi: 10.3389/fonc.2019.00965

[40] Sebti SM. Protein farnesylation: Implications for normal physiology, malignant transformation, and cancer therapy. Cancer Cell. 2005; 7(4):297-300. doi: 10.1016/j.ccr.2005.04.005

[41] Sobocińska J, Roszczenko-Jasińska P, Ciesielska A, Kwiatkowska K. Protein palmitoylation and its role in bacterial and viral infections. Front Immunol. 2018; 8:2003. doi: 10.3389/fimmu.2017.02003

[42] Das T, Yount JS, Hang HC. Protein S-palmitoylation in immunity. Open Biol. 2021; 11(3):200411. doi: 10.1098/rsob.200411

[43] Guan X, Fierke CA. Understanding protein palmitoylation: Biological significance and enzymology. Sci China Chem. 2011; 54(12):1888-1897. doi: 10.1007/s11426-011-4428-2

[44] Wang Y, Wang F. Post-Translational modifications of deubiquitinating enzymes: Expanding the ubiquitin code. Front Pharmacol. 2021; 12:685011. doi: 10.3389/fphar.2021.685011

[45] Grillari J, Grillari-Voglauer R, Jansen-Dürr P. Madame curie bioscience database. In: Post-Translational Modification of Cellular Proteins by Ubiquitin and Ubiquitin-Like Molecules:Role in Cellular Senescence and Ageing. Austin, TX: Landes Bioscience; 2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK28487

[46] Wang Y, Shi M, Feng H, et al. Structural insights into non-canonical ubiquitination catalyzed by side. Cell. 2018; 173(5):1231-1243.e16. doi: 10.1016/j.cell.2018.04.023

[47] Cherfils J, Zeghouf M. Regulation of small GTPASes by GEFs, GAPs, and GDIs. Physiol Rev. 2013; 93(1):269-309. doi: 10.1152/physrev.00003.2012

[48] Rowinsky EK, Windle JJ, Von Hoff DD. RAS protein farnesyltransferase: A strategic target for anticancer therapeutic development. J Clin Oncol. 1999; 17(11):3631-3652. doi: 10.1200/jco.1999.17.11.3631

[49] Rane N, Prendergast GC. Farnesyltransferase inhibitors: Mechanism and applications. Expert Opin Investig Drugs. 2001; 10(12):2105-2116. doi: 10.1517/13543784.10.12.2105

[50] Oh SH, Kim WY, Kim JH, et al. Identification of insulin-like growth factor binding protein-3 as a farnesyl transferase inhibitor SCH66336-induced negative regulator of angiogenesis in head and neck squamous cell carcinoma. Clin Cancer Res. 2006; 12(2):653-661. doi: 10.1158/1078-0432.ccr-05-1725

[51] Kelland LR, Smith V, Valenti M, et al. Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer. Clin Cancer Res. 2001; 7(11):3544-3550.

[52] Martin LA, Head JE, Pancholi S, et al. The farnesyltransferase inhibitor R115777 (tipifarnib) in combination with tamoxifen acts synergistically to inhibit MCF-7 breast cancer cell proliferation and cell cycle progression in vitro and in vivo. Mol Cancer Ther. 2007; 6(9):2458-2467. doi: 10.1158/1535-7163.mct-06-0452

[53] Cadelis MM, Bourguet-Kondracki ML, Dubois J, Valentin A, Barker D, Copp BR. Discovery and preliminary structure-activity relationship studies on tecomaquinone I and tectol as novel farnesyltransferase and plasmodial inhibitors. Bioorg Med Chem. 2016; 24(14):3102-3107. doi: 10.1016/j.bmc.2016.05.024

[54] Hedvat M, Huszar D, Herrmann A, et al. The JAK2 inhibitor AZD1480 potently blocks STAT3 signaling and oncogenesis in solid tumors. Cancer Cell. 2009; 16(6):487-497. doi: 10.1016/j.ccr.2009.10.015

[55] Hosseini A, Gharibi T, Marofi F, Javadian M, Babaloo Z, Baradaran B. Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases. J Cell Physiol. 2020; 235(9):5903-5924. doi: 10.1002/jcp.29593

[56] Aittomäki S, Pesu M. Therapeutic targeting of the JAK/STAT pathway. Basic Clin Pharmacol Toxicol. 2013; 114(1):18-23. doi: 10.1111/bcpt.12164

[57] Hu Y, Hong Y, Xu Y, Liu P, Guo DH, Chen Y. Inhibition of the JAK/STAT pathway with ruxolitinib overcomes cisplatin resistance in non-small-cell lung cancer NSCLC. Apoptosis. 2014; 19(11):1627-1636. doi: 10.1007/s10495-014-1030-z

[58] Lin CM, Cooles FA, Isaacs JD. Basic mechanisms of JAK inhibition. Mediterr J Rheumatol. 2020; 31(Suppl 1):100-104. doi: 10.31138/mjr.31.1.100

[59] Gill K, Kumar R, Mohanti BK, Dey S. Assessment of p38α in peripheral blood mononuclear cells (PBMC): A potential blood protein marker of head and neck squamous cell carcinoma. Clin Transl Oncol. 2013; 15(11):969-973. doi: 10.1007/s12094-013-1031-3

[60] Monnerat C, Henriksson R, Chevalier TL, et al. Phase I study of PKC412 (N-benzoyl-staurosporine), a novel oral protein kinase C inhibitor, combined with gemcitabine and cisplatin in patients with non-small-cell lung cancer. Ann Oncol. 2004; 15(2):316-323. doi: 10.1093/annonc/mdh052

[61] Lee D, Kwak HJ, Kim BH, et al. Brevilin A isolated from Centipeda minima induces apoptosis in human gastric cancer cells via an extrinsic apoptotic signaling pathway. Plants (Basel). 2022; 11(13):1658. doi: 10.3390/plants11131658

[62] Chen X, Du Y, Nan J, et al. Brevilin A, a novel natural product, inhibits janus kinase activity and blocks STAT3 signaling in cancer cells. PLoS One. 2013; 8(5):e63697. doi: 10.1371/journal.pone.0063697

[63] Khan M, Maryam A, Saleem MZ, et al. Brevilin A induces ROS-dependent apoptosis and suppresses STAT3 activation by direct binding in human lung cancer cells. J Cancer. 2020; 11(13):3725-3735. doi: 10.7150/jca.40983

[64] Guan X. Cancer metastases: Challenges and opportunities. Acta Pharm Sin B. 2015; 5(5):402-418. doi: 10.1016/j.apsb.2015.07.005

[65] Mitra SK, Schlaepfer DD. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol. 2006; 18(5):516-523. doi: 10.1016/j.ceb.2006.08.011

[66] Augoff K, Hryniewicz-Jankowska A, Tabola R. Invadopodia: Clearing the way for cancer cell invasion. Ann Transl Med. 2020; 8(14):902. doi: 10.21037/atm.2020.02.157

[67] Windham TC, Parikh NU, Siwak DR, et al. Src activation regulates anoikis in human colon tumor cell lines. Oncogene. 2002; 21(51):7797-7807. doi: 10.1038/sj.onc.1205989

[68] Playford MP, Schaller MD. The interplay between Src and integrins in normal and tumor biology. Oncogene. 2004; 23(48):7928-7946. doi: 10.1038/sj.onc.1208080

[69] Leong HS, Robertson AE, Stoletov K, et al. Invadopodia are required for cancer cell extravasation and are a therapeutic target for metastasis. Cell Rep. 2014; 8(5):1558-1570. doi: 10.1016/j.celrep.2014.07.050

[70] Eckert MA, Lwin TM, Chang AT, et al. Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell. 2011; 19(3):372-386. doi: 10.1016/j.ccr.2011.01.036

[71] Campone M, Bondarenko I, Brincat S, et al. Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy. Ann Oncol. 2011; 23(3):610-617. doi: 10.1093/annonc/mdr261

[72] Gucalp A, Sparano JA, Caravelli J, et al. Phase II trial of saracatinib (AZD0530), an Oral SRC-inhibitor for the treatment of patients with hormone receptor-negative metastatic breast cancer. Clin Breast Cancer. 2011; 11(5):306-311. doi: 10.1016/j.clbc.2011.03.021

[73] Mackay HJ, Au HJ, McWhirter E, et al. A phase II trial of the Src kinase inhibitor saracatinib (AZD0530) in patients with metastatic or locally advanced gastric or Gastro Esophageal Junction (GEJ) adenocarcinoma: A trial of the PMH phase II consortium. Invest New Drugs. 2011; 30(3):1158-1163. doi: 10.1007/s10637-011-9650-4

[74] Lee S, Park S, Ryu JS, et al. c-Src inhibitor PP2 inhibits head and neck cancer progression through regulation of the epithelial-mesenchymal transition. Exp Biol Med (Maywood). 2022; 248(6):492-500. doi: 10.1177/15353702221139183

[75] Min HY, Jung Y, Park KH, Oh WK, Lee HY. Erybraedin A is a potential Src inhibitor that blocks the adhesion and viability of non-small-cell lung cancer cells. Biochem Biophys Res Commun. 2018; 502(1):145-151. doi: 10.1016/j.bbrc.2018.05.137

[76] Luo C, Ai J, Ren E, et al. Research progress on evodiamine, a bioactive alkaloid of Evodiae fructus: Focus on its anti-cancer activity and bioavailability (Review). Exp Ther Med. 2021; 22(5):1327. doi: 10.3892/etm.2021.10762

[77] Mohan V, Agarwal R, Singh RP. A novel alkaloid, evodiamine causes nuclear localization of cytochrome-c and induces apoptosis independent of p53 in human lung cancer cells. Biochem Biophys Res Commun. 2016; 477(4):1065-1071. doi: 10.1016/j.bbrc.2016.07.037

[78] Hong Z, Wang Z, Zhou B, et al. Effects of evodiamine on PI3K/Akt and MAPK/ERK signaling pathways in pancreatic cancer cells. Int J Oncol. 2020; 56:783-793. doi: 10.3892/ijo.2020.4956

[79] Ogasawara M, Matsunaga T, Takahashi S, Saiki I, Suzuki H. Anti-invasive and metastatic activities of evodiamine. Biol Pharm Bull. 2002; 25(11):1491-1493. doi: 10.1248/bpb.25.1491

[80] Yu H, Jin H, Gong W, Wang Z, Liang H. Pharmacological actions of multi-target-directed evodiamine. Molecules. 2013; 18(2):1826-1843. doi: 10.3390/molecules18021826

[81] Ren L, Lou Y, Sun M. The anti-tumor effects of evodiamine on oral squamous cell carcinoma (OSCC) through regulating advanced glycation end products (AGE)/receptor for advanced glycation end products (RAGE) pathway. Bioengineered. 2021; 12(1):5985-5995. doi: 10.1080/21655979.2021.1972082

[82] Lin L, Lv S, Ren H, et al. Evodiamine inhibits EPRS expression to regulate glutamate metabolism and proliferation of oral squamous cell carcinoma cells. Kaohsiung J Med Sci. 2024; 40(4):348-359. doi: 10.1002/kjm2.12803

[83] Ma Y, Liu Y, Wang Y, et al. The nanocomposite system comprising folic acid-modified graphene quantum dots loaded with evodiamine in the treatment of oral squamous cell carcinoma. Mater Des. 2022; 220:110838. doi: 10.1016/j.matdes.2022.110838

[84] Ma XN, Xie CL, Miao Z, Yang Q, Yang XW. An overview of chemical constituents from Alpinia species in the last six decades. RSC Adv. 2017; 7(23):14114-14144. doi: 10.1039/c6ra27830b

[85] Hua SZ, Luo JG, Wang XB, Wang JS, Kong LY. Two novel monoterpene-chalcone conjugates isolated from the seeds of Alpinia katsumadai. Bioorg Med Chem Lett. 2009; 19(10):2728-2730. doi: 10.1016/j.bmcl.2009.03.117

[86] You HL, Zhou B, Guo MJ, et al. Monoterpene-chalcone conjugates and diarylheptanoids isolated from the seeds of Alpinia katsumadai hayata with cytotoxic activity. Phytochemistry. 2024; 225:114197. doi: 10.1016/j.phytochem.2024.114197