Document Type : Research articles


1 Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran

2 Department of Advanced Therapy Medicinal Product, Breast Cancer Research Center, Motamed Cancer Institute, Academic Center for Education, Culture, and Research, Tehran, Iran Recombinant Vaccine Research Center, Tehran University of Medical Sciences, Tehran, Iran Immunotherapy Group, Institute of Pharmaceutical Science, Tehran University of Medical Science, Tehran, Iran


Background: Breast cancer is extensively studied for its resistance to chemotherapy. Therefore, finding efficient therapeutic agents is vital to increasing the survival rate of patients.
Objectives: Here, we conducted an in vitro study on the anti-tumor properties of Vinca herbacea extract on SKBR3 cells.
Methods: Apoptotic and anti-invasive activity of V. herbacea extract was studied using Annexin FITC-V kit and Matrigel invasive assay, respectively. The expression of angiogenesis genes (VEGFR-1, VEGFR-2, and VEGF-A), apoptotic-related genes (Bcl-2 and BAX), as well as metastatic genes (MMP2 and MMP9) were studied using real-time polymerase chain reaction.
Results: Vinca herbacea extract showed significant antiproliferative and cytotoxic effects on human breast cancer cells, compared to human embryonic kidney cells 293. Vinca herbacea extract had a great apoptosis-inducing potential in breast cancer cells by activating caspase-3 and increasing the BAX/Bcl-2 ratio. Vinca herbacea extract prevented cancer cell angiogenesis, marked by decreasing the expression level of angiogenesis-related genes, including VEGF, VEGFR-1, and VEGFR-2. In addition, V. herbacea extracts reduced cancer cell invasion and noticeably decreased the expression level of metastasis-associated genes, including MMP2 and MMP9.
Conclusion: Vinca herbacea extracts exhibited vigorous cytotoxic effects on SKBR3 cells by the alteration of apoptosis, cell adhesion, invasion, and angiogenesis.


  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):359-86. doi: 10.1002/ijc.29210. [PubMed: 25220842].
  2. Power EJ, Chin ML, Haq MM. Breast Cancer Incidence and Risk Reduction in the Hispanic Population. Cureus. 2018;10(2):1-12. doi: 10.7759/cureus.2235. [PubMed: 29713580].
  3. Sadeghipour E, Sahragard N, Sayebani MR, Mahdizadeh. Breast cancer detection based on a hybrid approach of firefly algorithm and intelligent systems. Indian J Fundam Appl Life Sci. 2015;5(1):468-72.
  4. Kashyap D, Pal D, Sharma R, Kumar Garg V, Goel N, Zaguia A, et al., Global Increase in Breast Cancer incidence: risk factors and preventive measures. Biomed Res Int. 2022;2022:1-16. doi: 10.1155/2022/9605439. [PubMed: 35480139].
  5. Rafiemanesh H, Salehiniya H, Lotfi Z. Breast Cancer in Iranian Woman: incidence by age group, morphology and trends.
  6. Asian Pac J Cancer Prev. 2016;17(3):1393-7. doi: 10.7314/apjcp.2016.17.3.1393. [PubMed: 27039778].
  7. Ghavami V, Mahmoudi M, Rahimi Foroushani A, Baghishani H, Homaei Shandiz F, Yaseri M. Long-term disease-free survival of non-metastatic Breast Cancer patients in Iran: a survival model with competing risks taking cure fraction and frailty into account. Asian Pac J Cancer Prev. 2017;18(10):2825-32. doi: 10.22034/APJCP.2017.18.10.2825. [PubMed: 29072428].
  8. Zahmatkesh B, Keramat A, Alavi N, Khosravi A, Kousha A, Ghanbari Motlaghet A, et al., Breast cancer trend in Iran from 2000 to 2009 and prediction till 2020 using a trend analysis method. Asian Pac J Cancer Prev. 2016;17(3):1493-8. doi: 10.7314/apjcp.2016.17.3.1493. [PubMed: 27039796].
  9. O'Shaughnessy J. Extending survival with chemotherapy in metastatic breast cancer. oncologist. 2005;10(3):20-9. doi: 10.1634/theoncologist.10-90003-20. [PubMed: 16368868].
  10. Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The different mechanisms of cancer drug resistance: a
  11. brief review. Adv Pharm Bull. 2017;7(3):339-48. doi: 10.15171/apb.2017.041. [PubMed: 29071215].
  12. Force J, Henrique Santos Leal J, McArthur HL. Checkpoint blockade strategies in the treatment of breast cancer: where we are and where we are heading. Curr Treat Options Oncol. 2019;20(4):1-14. doi: 10.1007/s11864-019-0634-5.
  13. Ponde N, Aftimos P, Piccart M. Antibody-drug conjugates in breast cancer: a comprehensive review. Curr Treat Options Oncol. 2019;20(5):1-22. doi: 10.1007/s11864-019-0633-6. [PubMed: 30931493].
  14. Coombes C, Page K, Salari R, Hastings PK, Armstrong A, Ahmed S, et al. Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-18-3663. [PubMed: 30992300].
  15. Ang E, Wewala N, Carroll R, Forgeson G, Anderson M, Fernando J, et al. Neoadjuvant chemotherapy in non-metastatic breast cancer a study on practice trends in a regional cancer treatment service. Intern Med J. 2020;50(3):315-21. doi: 10.1111/imj.14326. [PubMed: 30989751].
  16. Zaid H, Silbermannet M, Amash A, Gincel D, Abdel-Sattar E, Boke Sarikahya N. Medicinal plants and natural active compounds for cancer chemoprevention/chemotherapy.
  17. Evid Based Complement Alternat Med. 2017:1-2. doi: 10.1155/2017/7952417.
  18. Ognyanov I, Pyuskyulev B, Kompis I, Sticzay T, Spiteller G, Shamma M, et al. Alkaloids from Vinca herbacea W.K. X. The structures and stereochemistry of majdine and isomajdine. Tetrahedron. 1968;24(13):4641-8. doi: 10.1016/s0040-4020(01)98661-2. [PubMed: 5657073].
  19. Vachnadze V, Vachnadze N, Gogitidze N, Mushkiashvili N, Mchedlidze K. Biologically active alkaloids from rhizomes with roots of vinca herbacea waldst. Et Kit, growing in Georgia. Georgian Med News. 2017;271:122-7. [PubMed: 29099714].
  20. Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res. 1987;47(4):936-42. [PubMed: 3802100]
  21. Hayon T, Dvilansky A, Shpilberg O, Nathan I. Appraisal of the MTT-based assay as a useful tool for predicting drug chemosensitivity in leukemia. Leuk Lymphoma. 2003;44(11):
  22. -62. doi: 10.1080/1042819031000116607. [PubMed: 14738150].
  23. Du GJ, Zhang Z, Wen XD, Yu C, Calway T, Yuan CS. Epigallocatechin Gallate (EGCG) is the most effective cancer chemopreventive polyphenol in green tea. Nutrients. 2012;4(11):1679-91. doi: 10.3390/nu4111679. [PubMed: 23201840].
  24. Pereira FV, Ferreira-Guimarães CA, Paschoalin T, Scutti JAB, Melo FM, Silva LS, et al. A natural bacterial-derived product, the metalloprotease arazyme, inhibits metastatic murine melanoma by inducing MMP-8 cross-reactive antibodies. Plos One. 2014;9(4):1-11. doi: 10.1371/journal.pone.0096141. [PubMed: 24788523].
  25. Kumar S, Sharma VK, Yadav S, Dey S. Antiproliferative and apoptotic effects of black turtle bean extracts on human breast cancer cell line through extrinsic and intrinsic pathway. Chemistry Central journal. 2017;11(1):1-10. doi: 10.1371/journal.pone.0096141. [PubMed: 24788523].
  26. Alotaibi MR, Hassan ZK, Al-Rejaie SS, Alshammari MA, Almutairi MM, Alhoshani AR, et al., Characterization of apoptosis in a breast cancer cell line after il-10 silencing. Asian Pac J Cancer Prev. 2018;19(3):777-83. doi: 10.22034/APJCP.2018.19.3.777. [PubMed: 29582634].
  27. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495-516. doi: 10.1080/01926230701320337. [PubMed: 17562483].
  28. Mohammad RM, Muqbil I, Lowe L, Yedjou C, Hsu HY, Lin LT, et al., Broad targeting of resistance to apoptosis in cancer. Semin Cancer Biol. 2015;35:78-103. doi: 10.1016/j.semcancer.2015.03.001. [PubMed: 25936818].
  29. Pu X, Storr SJ, Zhang Y, Rakha EA, Green AR, Elliset IO, et al. Caspase-3 and caspase-8 expression in breast cancer: caspase-3 is associated with survival. Apoptosis. 2017;22(3):357-68. doi: 10.1007/s10495-016-1323-5. [PubMed: 27798717].
  30. Gulcin I, Beydemir S, Topal F, Gagua N, Bakuridze A, Bayram R, et al. Apoptotic, antioxidant and antiradical effects of majdine and isomajdine from Vinca herbacea Waldst. and kit. J Enzyme Inhib Med Chem. 2012;27(4):587-94. doi: 10.3109/14756366.2011.604318. [PubMed: 21883037].
  31. Findley HW, Gu L, Yeager AM, Zhou M. Expression and regulation of Bcl-2, Bcl-xl, and Bax correlate with p53 status and sensitivity to apoptosis in childhood acute lymphoblastic leukemia. Blood. 1997;89(8):2986-93. [PubMed: 9108419].
  32. Bashyam MD. Understanding cancer metastasis: an urgent need for using differential gene expression analysis. Cancer. 2002;94(6):1821-9. doi: 10.1002/cncr.10362. [PubMed: 11920546].
  33. D'Arrigo G, Navarro G, Di Meo C, Matricardi P, Torchilin V. Gellan gum nanohydrogel containing anti-inflammatory and anti-cancer drugs: a multi-drug delivery system for a combination therapy in cancer treatment. Eur J Pharm Biopharm. 2014;87(1):208-16. doi: 10.1016/j.ejpb.2013.11.001. [PubMed: 24215783].
  34. Winer A, Adams S, Mignatti P. Matrix metalloproteinase inhibitors in cancer therapy: turning past failures into future successes. Mol Cancer Ther. 2018;17(6):1147-55. doi: 10.1158/1535-7163.MCT-17-0646. [PubMed: 29735645].
  35. Lu J, Zhang K, Nam S, Anderson RA, Jove R, Wen W. Novel angiogenesis inhibitory activity in cinnamon extract blocks VEGFR2 kinase and downstream signaling. Carcinogenesis. 2010;31(3):481-8. doi: 10.1093/carcin/bgp292. [PubMed: 19969552].
  36. Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013;13(12):871-82. doi: 10.1038/nrc3627. [PubMed: 24263190].
  37. Abhinand CS, Raju R , Soumya SJ, Arya PS, Sudhakaran PR. VEGF-A/VEGFR2 signaling network in endothelial cells relevant to angiogenesis. J Cell Commun Signal. 2016;
  38. (4):347-54. doi: 10.1007/s12079-016-0352-8. [PubMed: 27619687].