Studi Bioinformatika Tanaman Genus Nigella terhadap Kanker Payudara Tipe Basal Berbasis Transkriptomik dan Farmakologi Jaringan

Saipul Maulana; Muhammad Sulaiman Zubair; Muhammad Azwar AR

doi:10.32382/mf.v22i1.2038

Penulis

Saipul Maulana Program Studi S-1 Farmasi, Fakultas Matematika dan Ilmu Pengetahuan Alam, Universitas Tadulako, Palu, Indonesia https://orcid.org/0000-0002-3481-1819
Muhammad Sulaiman Zubair Program Studi S-1 Farmasi, Fakultas Matematika dan Ilmu Pengetahuan Alam, Universitas Tadulako, Palu, Indonesia https://orcid.org/0000-0002-3065-0480
Muhammad Azwar AR Program Studi S-1 Farmasi, Fakultas Matematika dan Ilmu Pengetahuan Alam, Universitas Tadulako, Palu, Indonesia

DOI:

https://doi.org/10.32382/mf.v22i1.2038

Kata Kunci:

EGFR, Farmakologi Jaringan, Kanker Payudara Tipe Basal, Nigella genus, TNBC

Abstrak

A Multi-Target Bioinformatics Analysis of the Nigella Genus Against Basal-Type Breast Cancer: An Integrative Transcriptomic and Network Pharmacology Approach

Basal-type breast cancer (Triple-Negative Breast Cancer, TNBC) is an aggressive subtype characterized by poor prognosis and limited conventional therapeutic options due to the absence of hormone receptor and HER2 expressions. To address this challenge, this study aims to elucidate the molecular mechanisms of compounds derived from the Nigella genus against basal-type breast cancer using a Network Pharmacology approach integrated with transcriptomic data. This in silico experimental study began with the identification of 433 bioactive compounds from the Nigella genus retrieved from databases, which were predicted to target a total of 2,227 potential proteins. Transcriptomic analysis was performed using the GSE7904 dataset, comparing 18 basal-type breast cancer samples with 7 normal control samples. Statistical analysis identified 4,901 significantly Differentially Expressed Genes (DEGs). Venn diagram intersection analysis between the compound targets and DEGs revealed 996 overlapping genes, which were designated as potential candidate targets. Protein-Protein Interaction (PPI) network topology analysis identified EGFR (Epidermal Growth Factor Receptor) as the top hub protein with a degree value of 110, followed by SRC (108) and PIK3CA (70). Functional enrichment analysis (KEGG) validated EGFR as a critical receptor in TNBC, initiating oncogenic signaling pathways such as MAPK and PI3K-Akt that drive basal-type cancer cell proliferation. Bioactive compounds from Nigella were predicted to exert their effects by interacting with membrane receptors and inhibiting tyrosine kinase activity. Therapeutic intervention targeting EGFR using bioactive compounds from the Nigella genus therefore represents a promising strategy to overcome resistance and aggressiveness in basal-type breast cancer.

Kanker payudara tipe basal (Triple-Negative Breast Cancer/TNBC) merupakan subtipe agresif yang ditandai dengan prognosis buruk dan terbatasnya pilihan terapi konvensional akibat ketiadaan ekspresi reseptor hormon dan HER2. Untuk mengatasi tantangan ini, penelitian ini bertujuan menjelaskan mekanisme molekuler senyawa genus Nigella terhadap kanker payudara tipe basal menggunakan pendekatan Farmakologi Jaringan (Network Pharmacology) terintegrasi dengan data transkriptomik. Studi eksperimental in silico ini diawali dengan mengidentifikasi 433 senyawa bioaktif genus Nigella dari basis data, yang memprediksi total 2.227 target protein potensial. Analisis transkriptomik dilakukan pada dataset GSE7904, yang membandingkan 18 sampel kanker basal dengan 7 kontrol normal. Berdasarkan uji statistik, analisis ini berhasil mengidentifikasi total 4.901 Differentially Expressed Genes (DEGs) signifikan. Melalui analisis irisan diagram Venn antara kedua dataset, ditemukan 996 gen tumpang tindih yang ditetapkan sebagai target kandidat potensial. Analisis topologi jaringan Interaksi Protein-Protein (PPI) mengidentifikasi EGFR (Epidermal Growth Factor Receptor) sebagai protein kunci (hub gene) teratas dengan nilai derajat (degree) 110, diikuti oleh SRC (108) dan PIK3CA (70). Analisis fungsional (KEGG) memvalidasi bahwa EGFR merupakan reseptor esensial dalam TNBC, yang menginisiasi jalur sinyal onkogenik MAPK dan PI3K-Akt yang mendorong proliferasi sel kanker tipe basal. Senyawa bioaktif Nigella diprediksi bekerja dengan berinteraksi pada reseptor membran dan menghambat aktivitas tirosin kinase. Intervensi terapeutik yang menargetkan EGFR menggunakan senyawa bioaktif genus Nigella menjadi strategi pengobatan yang menjanjikan untuk mengatasi resistensi dan agresivitas kanker payudara tipe basal.

Referensi

Abu-Darwish MS, Efferth T. Medicinal Plants from Near East for Cancer Therapy. Front Pharmacol. 2018 Jan 31;9:56. doi:10.3389/fphar.2018.00056

Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011 Jul;121(7):2750–67. doi:10.1172/JCI45014

Pradeep PP, Mohanty B, Lobo CL, Balusamy SR, Shetty A, Perumalsamy H, et al. Harnessing the nutriceutics in early-stage breast cancer: mechanisms, combinational therapy, and drug delivery. J Nanobiotechnology. 2024 Sep 18;22(1):574. doi:10.1186/s12951-024-02815-8

Xu D, Ma Y, Zhao B, Li S, Zhang YU, Pan S, et al. Thymoquinone induces G2/M arrest, inactivates PI3K/Akt and nuclear factor-κB pathways in human cholangiocarcinomas both in vitro and in vivo. Oncol Rep. 2014 May;31(5):2063–70. doi:10.3892/or.2014.3059

Wang W, Zhai GQ, Xin M, Li J, Liao JJ, Liang J, et al. Integrated network pharmacology and transcriptomics to reveal the mechanism of Passiflora against depressive disorder: An observational study. Medicine (Baltimore). 2024 Oct 11;103(41):e39309. doi:10.1097/MD.0000000000039309 PubMed PMID: 39465851; PubMed Central PMCID: PMC11479432.

Dadandi MY, Kökdil G, İlçim A, Özbilgin B. Seed macro and micro morphology of the selected Nigella (Ranunculaceae) taxa from Turkey and their systematic significance. Biologia. 2009 Apr;64(2):261–70. doi:10.2478/s11756-009-0030-x

Abdel-Hamid NM, Abdel-Ghany MI, Nazmy MH, Amgad SW. Can methanolic extract of Nigella sativa seed affect glyco-regulatory enzymes in experimental hepatocellular carcinoma? Environ Health Prev Med. 2013 Jan;18(1):49–56. doi:10.1007/s12199-012-0292-8

Lang M, Borgmann M, Oberhuber G, Evstatiev R, Jimenez K, Dammann KW, et al. Thymoquinone attenuates tumor growth in ApcMin mice by interference with Wnt-signaling. Mol Cancer. 2013 Dec;12(1):41. doi:10.1186/1476-4598-12-41

Almatroodi SA, Almatroudi A, Alsahli MA, Khan AA, Rahmani AH. Thymoquinone, an Active Compound of Nigella sativa: Role in Prevention and Treatment of Cancer. CPB. 2020 Sep 21;21(11):1028–41. doi:10.2174/1389201021666200416092743

Koka PS, Mondal D, Schultz M, Abdel-Mageed AB, Agrawal KC. Studies on molecular mechanisms of growth inhibitory effects of thymoquinone against prostate cancer cells: role of reactive oxygen species. Exp Biol Med (Maywood). 2010 Jun;235(6):751–60. doi:10.1258/ebm.2010.009369

Kaseb AO, Chinnakannu K, Chen D, Sivanandam A, Tejwani S, Menon M, et al. Androgen receptor– and E2F-1–targeted thymoquinone therapy for hormone-refractory prostate cancer. Cancer Res. 2007 Aug 15;67(16):7782–8. doi:10.1158/0008-5472.can-07-1483

Kundu J, Choi BUY, Jeong CH, Kundu JK, Chun KS. Thymoquinone induces apoptosis in human colon cancer HCT116 cells through inactivation of STAT3 by blocking JAK2- and Src-mediated phosphorylation of EGF receptor tyrosine kinase. Oncol Rep. 2014 Aug;32(2):821–8. doi:10.3892/or.2014.3223

Fathy M, Nikaido T. In vivo attenuation of angiogenesis in hepatocellular carcinoma by Nigella sativa. Turk J Med Sci. 2018 Feb 23;48(1):178–86. doi:10.3906/sag-1701-86

Imani S, Wei C, Cheng J, Asaduzzaman Khan M, Fu S, Yang L, et al. MicroRNA-34a targets epithelial to mesenchymal transition-inducing transcription factors (EMT-TFs) and inhibits breast cancer cell migration and invasion. Oncotarget. 2017 Mar 28;8(13):21362–79. doi:10.18632/oncotarget.15214

Li ZY, Zhang Z, Cao XZ, Feng Y, Ren SS. Platinum-based neoadjuvant chemotherapy for triple-negative breast cancer: a systematic review and meta-analysis. J Int Med Res. 2020 Oct;48(10):300060520964340. doi:10.1177/0300060520964340

Gomathinayagam R, Ha JH, Jayaraman M, Song YS, Isidoro C, Dhanasekaran DN. Chemopreventive and Anticancer Effects of Thymoquinone: Cellular and Molecular Targets. J Cancer Prev. 2020 Sep 30;25(3):136–51. doi:10.15430/JCP.2020.25.3.136

Aslam A, Minshawi F, Almasmoum H, Almaimani R, Alsaegh A, Mahbub AA, et al. Exploring potential additive effects of 5-fluorouracil, thymoquinone, and coenzyme Q10 triple therapy on colon cancer cells in relation to glycolysis and redox status modulation. J Egypt Natl Canc Inst. 2025 Mar 10;37(1):7. doi:10.1186/s43046-025-00261-7

Alamri AM, Assiri AA, Yousuf A, Khan NU. Exploring Nigella Sativa’s medicinal capacity against skin cancer pathways using network pharmacology and molecular docking. Sci Rep. 2025 Oct 3;15(1):34609. doi:10.1038/s41598-025-18200-w

Dogra A, Mehta A, Doval DC. Are basal-like and non-basal-like triple-negative breast cancers really different? J Oncol. 2020 Mar 16;2020:4061063. doi:10.1155/2020/4061063

Barkat MA, Harshita, Ahmad J, Khan MA, Beg S, Ahmad FJ. Insights into the targeting potential of thymoquinone for therapeutic intervention against triple-negative breast cancer. Curr Drug Targets. 2018 Jan 5;19(1). doi:10.2174/1389450118666170612095959

Ünal TD, Hamurcu Z, Delibaşı N, Çınar V, Güler A, Gökçe S, et al. Thymoquinone inhibits proliferation and migration of MDA-MB-231 triple Negative Breast Cancer cells by suppressing autophagy, Beclin-1 and LC3. Anticancer Agents Med Chem. 2021;21(3):355–64. doi:10.2174/1871520620666200807221047

Leidy J, Khan A, Kandil D. Basal-Like Breast Cancer: Update on Clinicopathologic, Immunohistochemical, and Molecular Features. Archives of Pathology & Laboratory Medicine. 2014 Jan 1;138(1):37–43. doi:10.5858/arpa.2012-0439-RA

Lehmann BD, Pietenpol JA. Clinical implications of molecular heterogeneity in triple negative breast cancer. Breast. 2015 Nov;24 Suppl 2:S36-40. doi:10.1016/j.breast.2015.07.009

Woo CC, Hsu A, Kumar AP, Sethi G, Tan KHB. Thymoquinone inhibits tumor growth and induces apoptosis in a breast cancer xenograft mouse model: The role of p38 MAPK and ROS. PLoS One. 2013 Oct 2;8(10):e75356. doi:10.1371/journal.pone.0075356

Li H, Li T, Quang D, Guan Y. Network propagation predicts drug synergy in cancers. Cancer Res. 2018 Sep 15;78(18):5446–57. doi:10.1158/0008-5472.can-18-0740

Li S, Zhang B, Zhang N. Network target for screening synergistic drug combinations with application to traditional Chinese medicine. BMC Syst Biol. 2011 Jun 20;5 Suppl 1(Suppl 1):S10. doi:10.1186/1752-0509-5-S1-S10

Dilshad A, Abulkhair O, Nemenqani D, Tamimi W. Antiproliferative properties of methanolic extract of Nigella sativa against the MDA-MB-231 cancer cell line. Asian Pac J Cancer Prev. 2012;13(11):5839–42. doi:10.7314/apjcp.2012.13.11.5839

Ahmed MM. Dual Targeting of EGFR and Estrogen Receptor α by Plant-Derived Thymoquinone: An in Silico Docking, ADMET, and Molecular Dynamics Study or Breast Cancer Therapy. ejeba. 2026 Mar 1;3(2):188–202. doi:10.59324/ejeba.2026.3(2).15

Xu C, Jiang ZB, Shao L, Zhao ZM, Fan XX, Sui X, et al. β-Elemene enhances erlotinib sensitivity through induction of ferroptosis by upregulating lncRNA H19 in EGFR-mutant non-small cell lung cancer. Pharmacological Research. 2023 May;191:106739. doi:10.1016/j.phrs.2023.106739

Xie Q, Li F, Fang L, Liu W, Gu C. The Antitumor Efficacy of β ‐Elemene by Changing Tumor Inflammatory Environment and Tumor Microenvironment. Ni H, editor. BioMed Research International. 2020 Jan;2020(1):6892961. doi:10.1155/2020/6892961

Faysal M, Zehravi M, Al Amin M, Sweilam SH, Panigrahy UP, Khan AS, et al. Targeting key molecular mechanisms in triple-negative breast cancer therapies with natural compounds. Curr Pharm Des. 2025 Oct 14;32. doi:10.2174/0113816128411154250918060514

Khan A, Aldebasi YH, Alsuhaibani SA, Khan MA. Thymoquinone augments cyclophosphamide-mediated inhibition of cell proliferation in breast cancer cells. Asian Pac J Cancer Prev. 2019 Apr 29;20(4):1153–60. doi:10.31557/APJCP.2019.20.4.1153

Sutton KM, Greenshields AL, Hoskin DW. Thymoquinone, A bioactive component of black caraway seeds, causes G1 phase cell cycle arrest and apoptosis in triple-negative breast cancer cells with mutant p53. Nutr Cancer. 2014 Apr 3;66(3):408–18. doi:10.1080/01635581.2013.878739

Dastjerdi M, Mehdiabady E, Iranpour F, Bahramian H. Effect of thymoquinone on P53 gene expression and consequence apoptosis in breast cancer cell line. Int J Prev Med. 2016;7(1):66. doi:10.4103/2008-7802.180412

Syahril F, Wirdah A, Nur Qodir, Irfanuddin, Irsan Saleh, Yenny Dian Andayani, et al. Effectiveness of Nigella sativa Addition against TNF-Alpha in Stage III and IV Breast Cancer Undergoing Doxorubicin and Cyclophosphamide Chemotherapy at Dr. Mohammad Hoesin General Hospital, Palembang, Indonesia. Bioscmed. 2023 Dec 12;8(2):4009–14. doi:10.37275/bsm.v8i2.924

Scognamiglio M, Maresca V, Basile A, Pacifico S, Fiorentino A, Bruno M, et al. Phytochemical Characterization, Antioxidant, and Anti-Proliferative Activities of Wild and Cultivated Nigella damascena Species Collected in Sicily (Italy). Antioxidants. 2024 Mar 27;13(4):402. doi:10.3390/antiox13040402

Salehi B, Quispe C, Imran M, Ul-Haq I, Živković J, Abu-Reidah IM, et al. Nigella Plants – Traditional Uses, Bioactive Phytoconstituents, Preclinical and Clinical Studies. Front Pharmacol. 2021 Apr 26;12:625386. doi:10.3389/fphar.2021.625386

Shabani H, Karami MH, Kolour J, Sayyahi Z, Parvin MA, Soghala S, et al. Anticancer activity of thymoquinone against breast cancer cells: Mechanisms of action and delivery approaches. Biomedicine & Pharmacotherapy. 2023 Sep;165:114972. doi:10.1016/j.biopha.2023.114972

Orrantia-Borunda E, Anchondo-Nuñez P, Acuña-Aguilar LE, Gómez-Valles FO, Ramírez-Valdespino CA. Subtypes of Breast Cancer. In: Breast Cancer [Internet]. Exon Publications; 2022. p. 31–42. Available from: http://dx.doi.org/10.36255/exon-publications-breast-cancer-subtypes doi:10.36255/exon-publications-breast-cancer-subtypes

Cruz-Gordillo P, Honeywell ME, Harper NW, Leete T, Lee MJ. ELP-dependent expression of MCL1 promotes resistance to EGFR inhibition in triple-negative breast cancer cells. Sci Signal. 2020 Nov 17;13(658):eabb9820. doi:10.1126/scisignal.abb9820

Heideman MR, Hynes NE. AXL/epidermal growth factor receptor (EGFR) complexes in breast cancer - culprits for resistance to EGFR inhibitors? Breast Cancer Res. 2013 Oct;15(5):315. doi:10.1186/bcr3564

Rajput S, Kumar BNP, Dey KK, Pal I, Parekh A, Mandal M. Molecular targeting of Akt by thymoquinone promotes G1 arrest through translation inhibition of cyclin D1 and induces apoptosis in breast cancer cells. Life Sci. 2013 Nov;93(21):783–90. doi:10.1016/j.lfs.2013.09.009

Arafa ESA, Zhu Q, Shah ZI, Wani G, Barakat BM, Racoma I, et al. Thymoquinone up-regulates PTEN expression and induces apoptosis in doxorubicin-resistant human breast cancer cells. Mutat Res. 2011 Jan 10;706(1–2):28–35. doi:10.1016/j.mrfmmm.2010.10.007