Virtual screening of natural compounds as combinatorial agents from indian medicinal plants against estrogen positive breast cancer
Abstract
Facing worldwide challenges associated with multifactorial etiology of breast cancer, designing of combinatorial therapies using natural compounds is currently the emergent way of treating several cancers including breast cancer in a synergistic way, which may mitigate several problems associated with multiple receptor targeting. In this research, Estrogen receptor positive breast cancer was taken as prototype and several key receptors associated with this particular disease were targeted by virtual screening of natural compounds found in Indian originated medicinal plants using Computer aided Drug Designing (CADD) strategies. We found the combination of Carpusin, Paulownin Cornigerine, Nororientaline, Oryzalexin B, Romucosine H and Colchicine as effective against six potential receptors i.e. FGFR2, ESR1, PIK3CA, PIK3CB, PIK3CD and AR in Estrogen receptor positive breast cancer with their binding energies in the range of ∆G ≤ -8.0 Kcal/mol as well as significant number of common amino acid binding residues as compared with binding sites of receptors. Thus this research holds significant implications for the designing of combinatorial therapeutic agents against breast cancer which can be further tested in-vitro and in-vivo to prove their synergistic efficiency.
References
T. N. Toporcov and V. Wünsch Filho, “Epidemiological science and cancer control,” Clinics, vol. 73, no. Suppl 1. Universidade de Sao Paulo, 2018, doi: 10.6061/clinics/2018/e627s.
Z. Momenimovahed and H. Salehiniya, “Epidemiological characteristics of and risk factors for breast cancer in the world,” Breast Cancer: Targets and Therapy, vol. 11. Dove Medical Press Ltd., pp. 151–164, 2019, doi: 10.2147/BCTT.S176070.
S. De Silva, K. H. Tennekoon, and E. H. Karunanayake, “Overview of the genetic basis toward early detection of breast cancer,” Breast Cancer: Targets and Therapy, vol. 11. Dove Medical Press Ltd., pp. 71–80, 2019, doi: 10.2147/BCTT.S185870.
J. Clavel, “Progress in the epidemiological understanding of gene-environment interactions in major diseases: cancer,” Comptes Rendus - Biologies, vol. 330, no. 4. Inserm, pp. 306–317, Apr. 2007, doi: 10.1016/j.crvi.2007.02.012.
M. L. Wan et al., “Colorectal cancer (CRC) as a multifactorial disease and its causal correlations with multiple signaling pathways,” Bioscience Reports, vol. 40, no. 3. Portland Press Ltd, 2020, doi: 10.1042/BSR20200265.
“Projections of number of cancer cases in India (2010-2020) by cancer groups - PubMed.” https://pubmed.ncbi.nlm.nih.gov/21133622/ (accessed Aug. 16, 2020).
“WHO | Breast cancer: prevention and control,” WHO, 2016, Accessed: Aug. 16, 2020. [Online]. Available: http://www.who.int/cancer/detection/breastcancer/en/.
N. Azamjah, Y. Soltan-Zadeh, and F. Zayeri, “Global trend of breast cancer mortality rate: A 25-year study,” Asian Pacific J. Cancer Prev., vol. 20, no. 7, pp. 2015–2020, 2019, doi: 10.31557/APJCP.2019.20.7.2015.
S. Rajpal, A. Kumar, and W. Joe, “Economic burden of cancer in India: Evidence from cross-sectional nationally representative household survey, 2014,” PLoS One, vol. 13, no. 2, Feb. 2018, doi: 10.1371/journal.pone.0193320.
G. Mathew et al., “Community-based burden, warning signs, and risk factors of cancer using public-private partnership model in Kerala, India,” J. Fam. Med. Prim. Care, vol. 9, no. 2, p. 745, 2020, doi: 10.4103/jfmpc.jfmpc_1030_19.
P. Mathur et al., “Cancer Statistics, 2020: Report From National Cancer Registry Programme, India.,” JCO Glob. Oncol., vol. 6, no. 6, pp. 1063–1075, Jul. 2020, doi: 10.1200/GO.20.00122.
J. Zhang, Y. Deng, and B. L. Khoo, “Fasting to enhance Cancer treatment in models: The next steps,” Journal of Biomedical Science, vol. 27, no. 1. BioMed Central Ltd., May 05, 2020, doi: 10.1186/s12929-020-00651-0.
K. L. Cheung, “Treatment strategies and survival outcomes in breast cancer,” Cancers, vol. 12, no. 3. MDPI AG, Mar. 01, 2020, doi: 10.3390/cancers12030735.
S. Y. Wang, H. Z. Hu, X. C. Qing, Z. C. Zhang, and Z. W. Shao, “Recent advances of drug delivery nanocarriers in osteosarcoma treatment,” Journal of Cancer, vol. 11, no. 1. Ivyspring International Publisher, pp. 69–82, 2020, doi: 10.7150/jca.36588.
W. Scarano, P. De Souza, and M. H. Stenzel, “Dual-drug delivery of curcumin and platinum drugs in polymeric micelles enhances the synergistic effects: A double act for the treatment of multidrug-resistant cancer,” Biomater. Sci., vol. 3, no. 1, pp. 163–174, Jan. 2015, doi: 10.1039/c4bm00272e.
Q. Mu et al., “Novel drug combination nanoparticles exhibit enhanced plasma exposure and dose-responsive effects on eliminating breast cancer lung metastasis,” PLoS One, vol. 15, no. 3, 2020, doi: 10.1371/journal.pone.0228557.
J. Y. Choi, R. K. Thapa, C. S. Yong, and J. O. Kim, “Nanoparticle-based combination drug delivery systems for synergistic cancer treatment,” Journal of Pharmaceutical Investigation, vol. 46, no. 4. Springer Netherlands, pp. 325–339, Jul. 01, 2016, doi: 10.1007/s40005-016-0252-1.
E. Moujaess, H. R. Kourie, and M. Ghosn, “Cancer patients and research during COVID-19 pandemic: A systematic review of current evidence,” Critical Reviews in Oncology/Hematology, vol. 150. Elsevier Ireland Ltd, p. 102972, Jun. 01, 2020, doi: 10.1016/j.critrevonc.2020.102972.
H. Vatansev, C. Kadiyoran, M. Cumhur Cure, and E. Cure, “COVID-19 infection can cause chemotherapy resistance development in patients with breast cancer and tamoxifen may cause susceptibility to COVID-19 infection,” Medical Hypotheses, vol. 143. Churchill Livingstone, p. 110091, Oct. 01, 2020, doi: 10.1016/j.mehy.2020.110091.
A. M. L. Seca and D. C. G. A. Pinto, “Plant secondary metabolites as anticancer agents: Successes in clinical trials and therapeutic application,” International Journal of Molecular Sciences, vol. 19, no. 1. MDPI AG, Jan. 16, 2018, doi: 10.3390/ijms19010263.
A. Agbarya, N. Ruimi, R. Epelbaum, E. Ben-Arye, and J. Mahajna, “Natural products as potential cancer therapy enhancers: A preclinical update,” SAGE Open Med., vol. 2, p. 205031211454692, Jan. 2014, doi: 10.1177/2050312114546924.
S. S. Bashraheel, A. Domling, and S. K. Goda, “Update on targeted cancer therapies, single or in combination, and their fine tuning for precision medicine,” Biomedicine and Pharmacotherapy, vol. 125. Elsevier Masson SAS, May 01, 2020, doi: 10.1016/j.biopha.2020.110009.
A. F. Herrera et al., “Safety and activity of ibrutinib in combination with durvalumab in patients with relapsed or refractory follicular lymphoma or diffuse large B-cell lymphoma,” Am. J. Hematol., vol. 95, no. 1, pp. 18–27, Jan. 2020, doi: 10.1002/ajh.25659.
F. A. Fisusi and E. O. Akala, “Drug Combinations in Breast Cancer Therapy,” Pharm. Nanotechnol., vol. 7, no. 1, pp. 3–23, Jan. 2019, doi: 10.2174/2211738507666190122111224.
T. K. Burki, “Fulvestrant plus anastrozole for metastatic breast cancer,” The Lancet. Oncology, vol. 20, no. 5. NLM (Medline), p. e247, May 01, 2019, doi: 10.1016/S1470-2045(19)30217-7.
K. H. Jung et al., “Targeted therapy of triple negative MDA-MB-468 breast cancer with curcumin delivered by epidermal growth factor-conjugated phospholipid nanoparticles,” Oncol. Lett., vol. 15, no. 6, pp. 9093–9100, Jun. 2018, doi: 10.3892/ol.2018.8471.
B. Noel, S. K. Singh, J. W. Lillard, and R. Singh, “Role of natural compounds in preventing and treating breast cancer,” Front. Biosci. - Sch., vol. 12, no. 1, pp. 137–160, Mar. 2020, doi: 10.2741/S544.
A. Lodi et al., “Combinatorial treatment with natural compounds in prostate cancer inhibits prostate tumor growth and leads to key modulations of cancer cell metabolism,” npj Precis. Oncol., vol. 1, no. 1, Dec. 2017, doi: 10.1038/s41698-017-0024-z.
V. Shriram, T. Khare, R. Bhagwat, R. Shukla, and V. Kumar, “Inhibiting bacterial drug efflux pumps via phyto-therapeutics to combat threatening antimicrobial resistance,” Front. Microbiol., vol. 9, no. DEC, Dec. 2018, doi: 10.3389/fmicb.2018.02990.
I. Górniak, R. Bartoszewski, and J. Króliczewski, “Comprehensive review of antimicrobial activities of plant flavonoids,” Phytochemistry Reviews, vol. 18, no. 1. Springer Netherlands, pp. 241–272, Feb. 15, 2019, doi: 10.1007/s11101-018-9591-z.
L. Wang et al., “Wnt1-inducible signaling protein 1 regulates laryngeal squamous cell carcinoma glycolysis and chemoresistance via the YAP1/TEAD1/GLUT1 pathway,” J. Cell. Physiol., vol. 234, no. 9, pp. 15941–15950, Sep. 2019, doi: 10.1002/jcp.28253.
A. Moore and R. Pinkerton, “Vincristine: Can its therapeutic index be enhanced?,” Pediatr. Blood Cancer, vol. 53, no. 7, pp. 1180–1187, Dec. 2009, doi: 10.1002/pbc.22161.
S. R. Lin et al., “Natural compounds as potential adjuvants to cancer therapy: Preclinical evidence,” British Journal of Pharmacology, vol. 177, no. 6. John Wiley and Sons Inc., pp. 1409–1423, Mar. 01, 2020, doi: 10.1111/bph.14816.
S. Mitra and R. Dash, “Natural Products for the Management and Prevention of Breast Cancer,” Evidence-based Complementary and Alternative Medicine, vol. 2018. Hindawi Limited, 2018, doi: 10.1155/2018/8324696.
R. Dembinski et al., “Estrogen Receptor Positive and Progesterone Receptor Negative Breast Cancer: the Role of Hormone Therapy,” Horm. Cancer, vol. 11, no. 3–4, pp. 148–154, Aug. 2020, doi: 10.1007/s12672-020-00387-1.
F. Lumachi, “Current medical treatment of estrogen receptor-positive breast cancer,” World J. Biol. Chem., vol. 6, no. 3, p. 231, 2015, doi: 10.4331/wjbc.v6.i3.231.
D. Lüftner et al., “Update Breast Cancer 2020 Part 2 - Advanced Breast Cancer: New Treatments and Implementation of Therapies with Companion Diagnostics,” Geburtshilfe Frauenheilkd., vol. 80, no. 4, pp. 391–398, Apr. 2020, doi: 10.1055/a-1111-8775.
“FGFR2 fibroblast growth factor receptor 2 [Homo sapiens (human)] - Gene - NCBI.” https://www.ncbi.nlm.nih.gov/gene/2263 (accessed Aug. 14, 2020).
S. Navid, C. Fan, P. O. Flores-Villanueva, D. Generali, and Y. Li, “The fibroblast growth factor receptors in breast cancer: From oncogenesis to better treatments,” International Journal of Molecular Sciences, vol. 21, no. 6. MDPI AG, Mar. 02, 2020, doi: 10.3390/ijms21062011.
“ESR1 estrogen receptor 1 [Homo sapiens (human)] - Gene - NCBI.” https://www.ncbi.nlm.nih.gov/gene/2099 (accessed Aug. 14, 2020).
F. Clatot et al., “Risk of early progression according to circulating ESR1 mutation, CA-15.3 and cfDNA increases under first-line anti-aromatase treatment in metastatic breast cancer,” Breast Cancer Res., vol. 22, no. 1, May 2020, doi: 10.1186/s13058-020-01290-x.
A. Zundelevich et al., “ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis,” Breast Cancer Res., vol. 22, no. 1, p. 16, Feb. 2020, doi: 10.1186/s13058-020-1246-5.
“AR androgen receptor [Homo sapiens (human)] - Gene - NCBI.” https://www.ncbi.nlm.nih.gov/gene/367 (accessed Aug. 14, 2020).
C. Amaral, T. V. Augusto, M. Almada, S. C. Cunha, G. Correia-da-Silva, and N. Teixeira, “The potential clinical benefit of targeting androgen receptor (AR) in estrogen-receptor positive breast cancer cells treated with Exemestane,” Biochim. Biophys. Acta - Mol. Basis Dis., vol. 1866, no. 5, May 2020, doi: 10.1016/j.bbadis.2019.165661.
K. H. Kensler et al., “Prognostic and predictive value of androgen receptor expression in postmenopausal women with estrogen receptor-positive breast cancer: Results from the Breast International Group Trial 1-98,” Breast Cancer Res., vol. 21, no. 1, p. 30, Feb. 2019, doi: 10.1186/s13058-019-1118-z.
H. Qin et al., “The impact of PI3K inhibitors on breast cancer cell and its tumor microenvironment,” PeerJ, vol. 2018, no. 6, 2018, doi: 10.7717/peerj.5092.
“PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [Homo sapiens (human)] - Gene - NCBI.” https://www.ncbi.nlm.nih.gov/gene/5290 (accessed Aug. 14, 2020).
“PIK3CB phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [Homo sapiens (human)] - Gene - NCBI.” https://www.ncbi.nlm.nih.gov/gene/5291 (accessed Aug. 14, 2020).
“PIK3CD phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [Homo sapiens (human)] - Gene - NCBI.” https://www.ncbi.nlm.nih.gov/gene/5293 (accessed Aug. 14, 2020).
R. J. Crowder et al., “PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer,” Cancer Res., vol. 69, no. 9, pp. 3955–3962, May 2009, doi: 10.1158/0008-5472.CAN-08-4450.
D. Huang, L. Tang, F. Yang, J. Jin, and X. Guan, “PIK3CA mutations contribute to fulvestrant resistance in ER-positive breast cancer.,” Am. J. Transl. Res., vol. 11, no. 9, pp. 6055–6065, 2019, Accessed: Aug. 12, 2020. [Online]. Available: http://www.ncbi.nlm.nih.gov/pubmed/31632573.
B. Verret, J. Cortes, T. Bachelot, F. Andre, and M. Arnedos, “Efficacy of PI3K inhibitors in advanced breast cancer,” Annals of oncology : official journal of the European Society for Medical Oncology, vol. 30, no. 10. NLM (Medline), pp. x12–x20, Dec. 01, 2019, doi: 10.1093/annonc/mdz381.
J. S. Chen et al., “PIK3CD induces cell growth and invasion by activating AKT/GSK-3β/β-catenin signaling in colorectal cancer,” Cancer Sci., vol. 110, no. 3, pp. 997–1011, Mar. 2019, doi: 10.1111/cas.13931.
E. G. Puigjané, “A new ligand-based approach to virtual screening and profiling of large chemical libraries,” p. 172, 2008.
W. Cui, A. Aouidate, S. Wang, Q. Yu, Y. Li, and S. Yuan, “Discovering Anti-Cancer Drugs via Computational Methods,” Frontiers in Pharmacology, vol. 11. Frontiers Media S.A., May 20, 2020, doi: 10.3389/fphar.2020.00733.
T. Bintener, M. P. Pacheco, and T. Sauter, “Towards the routine use of in silico screenings for drug discovery using metabolic modelling,” Biochem. Soc. Trans., vol. 48, no. 3, pp. 955–969, Jun. 2020, doi: 10.1042/BST20190867.
Z. Zhang et al., “Overcoming cancer therapeutic bottleneck by drug repurposing,” Signal Transduction and Targeted Therapy, vol. 5, no. 1. Springer Nature, Dec. 01, 2020, doi: 10.1038/s41392-020-00213-8.
A. H. Ananth et al., “Design, Synthesis, and Biological Evaluation of 2-(2-Bromo-3-nitrophenyl)-5-phenyl-1,3,4-oxadiazole Derivatives as Possible Anti-Breast Cancer Agents,” Chem. Biodivers., vol. 17, no. 2, Feb. 2020, doi: 10.1002/cbdv.201900659.
X. Lu et al., “A new class of 1,3,5-triazine-based selective estrogen receptor degraders (SERDs): Lead optimization, molecular docking and dynamic simulation,” Bioorg. Chem., vol. 97, Apr. 2020, doi: 10.1016/j.bioorg.2020.103666.
N. T. Nguyen et al., “Autodock Vina Adopts More Accurate Binding Poses but Autodock4 Forms Better Binding Affinity,” J. Chem. Inf. Model., vol. 60, no. 1, pp. 204–211, Jan. 2020, doi: 10.1021/acs.jcim.9b00778.
S. Dallakyan and A. J. Olson, “Small-molecule library screening by docking with PyRx,” Methods Mol. Biol., vol. 1263, pp. 243–250, 2015, doi: 10.1007/978-1-4939-2269-7_19.
B. H. M. Mooers, “Simplifying and enhancing the use of PyMOL with horizontal scripts,” Protein Sci., vol. 25, no. 10, pp. 1873–1882, Oct. 2016, doi: 10.1002/pro.2996.
K. Mohanraj et al., “IMPPAT: A curated database of Indian Medicinal Plants, Phytochemistry and Therapeutics,” Sci. Rep., vol. 8, no. 1, Dec. 2018, doi: 10.1038/s41598-018-22631-z.
P. J et al., “DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants,” Nucleic Acids Res., vol. 45, no. D1, 2017, doi: 10.1093/NAR/GKW943.
D. Szklarczyk et al., “STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets,” Nucleic Acids Res., vol. 47, no. D1, pp. D607–D613, Jan. 2019, doi: 10.1093/nar/gky1131.
W. Liu et al., “Discovery, Identification and Comparative Analysis of Non-Specific Lipid Transfer Protein (nsLtp) Family in Solanaceae,” Genomics, Proteomics Bioinforma., vol. 8, no. 4, pp. 229–237, Dec. 2010, doi: 10.1016/S1672-0229(10)60024-1.
“Vina output analysis using Discovery Studio visualizer - Bioinformatics Review.” https://bioinformaticsreview.com/20191101/vina-output-analysis-using-discovery-studio-visualizer/ (accessed Aug. 15, 2020).
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