Ferdowsi University of Mashhad

Document Type : Review / Mini-Review


Department of Biology, Faculty of Sciences, Hakim Sabzevari University, Iran


The use of medicinal plants in the treatment of diseases has a long history dating back to the presence of humans on earth. Cancer has almost been an incurable disease, and among the various cancers, breast cancer is the most common type of cancer among women and imposes an enormous burden on patients. Although medical and surgical solutions have been proposed for the disease, it has not been successful enough to treat the disease in many patients. In recent years, more studies have been done on the effects of medicinal plants on breast cancer, and scientists are trying to find the exact mechanisms of action for these plants to find effective ways for controlling cancer cell growth.  This article focuses on P53 and MDM2, two very important genes involved in regulation of cell growth and proliferation both in cancer and normal tissue, and we also gathered the list of natural compounds targeting the MDM2-p53 pathway. Our results provide a list of plant families that can influence this pathway and have great potential in designing treatments against cancers that encompass deregulation of the MDM2-p53 pathway.


Baraya. Y. S., K. K. Wong and N. S. Yaacob (2017). The Immunomodulatory Potential of Selected Bioactive Plant-Based Compounds in Breast Cancer: A Review. Anticancer Agents Med Chem 17(6): 770-783.
Bellazzo. A., D. Sicari, E. Valentino, G. Del Sal and L. Collavin (2018). Complexes formed by mutant p53 and their roles in breast cancer. Breast Cancer (Dove Med Press) 10: 101-112.
Brekman. A., K. E. Singh, A. Polotskaia, N. Kundu and J. Bargonetti (2011). A p53-independent role of Mdm2 in estrogen-mediated activation of breast cancer cell proliferation. Breast Cancer Research 13(1): 1-14.
Brown. C. J., S. Lain, C. S. Verma, A. R. Fersht and D. P. Lane (2009). Awakening guardian angels: drugging the p53 pathway. Nature Reviews Cancer 9(12): 862-873.
Cabral. B. L. S., A. C. G. da Silva, R. I. de Avila, A. P. Cortez, R. M. Luzin, et al. (2017). A novel chalcone derivative, LQFM064, induces breast cancer cells death via p53, p21, KIT and PDGFRA. European Journal of Pharmaceutical Sciences 107: 1-15.
Chandler. D. S., R. K. Singh, L. C. Caldwell, J. L. Bitler and G. Lozano (2006). Genotoxic stress induces coordinately regulated alternative splicing of the p53 modulators MDM2 and MDM4. Cancer research 66(19): 9502-9508.
Choobkar. N., S. Kakoolaki and F. Mohammadi (2017). The biological effects of herbal medicine, Falcaria vulgaris: An article review. Iranian Journal of Aquatic Animal Health 3(1): 74-81.
Cicalese. A., G. Bonizzi, C. E. Pasi, M. Faretta, S. Ronzoni, B. Giulini, et al. (2009). The tumor suppressor p53 regulates polarity of self-renewing divisions in mammary stem cells. Cell 138(6): 1083-1095.
Cordon-Cardo. C., E. Latres, M. Drobnjak, M. R. Oliva, D. Pollack, J. M. Woodruff, et al. (1994). Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. Cancer research 54(3): 794-799.
de Oca Luna. R. M., D. S. Wagner and G. Lozano (1995). Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature 378(6553): 203-206.
Evans. S. C., M. Viswanathan, J. D. Grier, M. Narayana, A. K. El-Naggar and G. Lozano (2001). An alternatively spliced HDM2 product increases p53 activity by inhibiting HDM2. Oncogene 20(30): 4041-4049.
Gopal. Y. V., E. Chanchorn and M. W. Van Dyke (2009). Parthenolide promotes the ubiquitination of MDM2 and activates p53 cellular functions. Molecular cancer therapeutics 8(3): 552-562.
Gupta. A., K. Shah, M. J. Oza and T. Behl (2019). Reactivation of p53 gene by MDM2 inhibitors: A novel therapy for cancer treatment. Biomedicine & Pharmacotherapy 109: 484-492.
Hsu. Y.-L., Y.-H. Uen, Y. Chen, H.-L. Liang and P.-L. Kuo (2009). Tricetin, a dietary flavonoid, inhibits proliferation of human breast adenocarcinoma mcf-7 cells by blocking cell cycle progression and inducing apoptosis. Journal of agricultural and food chemistry 57(18): 8688-8695.
Key. T. J., P. K. Verkasalo and E. Banks (2001). Epidemiology of breast cancer. The lancet oncology 2(3): 133-140.
Khan. F., F. Ahmed, P. N. Pushparaj, A. Abuzenadah, T. Kumosani, E. Barbour, et al. (2016). Ajwa Date (Phoenix dactylifera L.) Extract Inhibits Human Breast Adenocarcinoma (MCF7) Cells In Vitro by Inducing Apoptosis and Cell Cycle Arrest. PLoS One 11(7): e0158963.
Kim. S., J. Han, N.-Y. Kim, S. K. Lee, D. H. Cho, M.-Y. Choi, et al. (2012). Effect of berberine on p53 expression by TPA in breast cancer cells. Oncology reports 27(1): 210-215.
Klei. C. and L. Vassilev (2004). Targeting the p53–MDM2 interaction to treat cancer. British journal of cancer 91(8): 1415-1419.
Kubatka. P., M. Kello, K. Kajo, M. Samec, K. Jasek, D. Vybohova, et al. (2020). Chemopreventive and Therapeutic Efficacy of Cinnamomum zeylanicum L. Bark in Experimental Breast Carcinoma: Mechanistic In Vivo and In Vitro Analyses. Molecules 25(6).
Kubatka. P., M. Kello, K. Kajo, M. Samec, A. Liskova, K. Jasek, et al. (2020). Rhus coriaria L. (Sumac) Demonstrates Oncostatic Activity in the Therapeutic and Preventive Model of Breast Carcinoma. Int J Mol Sci 22(1).
Kubatka. P., S. Uramova, M. Kello, K. Kajo, M. Samec, K. Jasek, et al. (2019). Anticancer Activities of Thymus vulgaris L. in Experimental Breast Carcinoma in Vivo and in Vitro. Int J Mol Sci 20(7).
Lane. D. P. (1992). p53, guardian of the genome. Nature 358(6381): 15-16.
Lang. S. J., M. Schmiech, S. Hafner, C. Paetz, K. Werner, M. El Gaafary, et al. (2020). Chrysosplenol d, a Flavonol from Artemisia annua, Induces ERK1/2-Mediated Apoptosis in Triple Negative Human Breast Cancer Cells. Int J Mol Sci 21(11).
Lee. E., H. To, J.-Y. Shew, R. Bookstein, P. Scully and W.-H. Lee (1988). Inactivation of the retinoblastoma susceptibility gene in human breast cancers. Science 241(4862): 218-221.
Lee. E. Y. and W. J. Muller (2010). Oncogenes and tumor suppressor genes. Cold Spring Harbor perspectives in biology 2(10): a003236.
Li. H., Q. Liu, Z. Wang, R. Fang, Y. Shen, X. Cai, Y. Gao, Y. Li, et al. (2015). The oncoprotein HBXIP modulates the feedback loop of MDM2/p53 to enhance the growth of breast cancer. Journal of Biological Chemistry 290(37): 22649-22661.
Li. M., Z. Zhang, D. L. Hill, X. Chen, H. Wang and R. Zhang (2005). Genistein, a dietary isoflavone, down-regulates the MDM2 oncogene at both transcriptional and posttranslational levels. Cancer Research 65(18): 8200-8208.
Liu. L., J. Yan, Y. Cao, Y. Yan, X. Shen, B. Yu, et al. (2021). Proliferation, migration and invasion of triple negative breast cancer cells are suppressed by berbamine via the PI3K/Akt/MDM2/p53 and PI3K/Akt/mTOR signaling pathways. Oncol Lett 21(1): 70.
McCann. A., A. Kirley, D. Carney, N. Corbally, H. Magee, G. Keating et al. (1995). Amplification of the MDM 2 gene in human breast cancer and its association with MDM2 and p53 protein status. British journal of cancer 71(5): 981-985.
McGrowder. D. A., F. G. Miller, C. R. Nwokocha, M. S. Anderson, C. Wilson-Clarke, K. Vaz, et al. (2020). Medicinal Herbs Used in Traditional Management of Breast Cancer: Mechanisms of Action." Medicines 7(8): 47.
Mitra. S. and R. Dash (2018). Natural Products for the Management and Prevention of Breast Cancer. Evidence-based Complementary and Alternative Medicine 2018: 23.
Nagamine. M. K., T. C. da Silva, P. Matsuzaki, K. C. Pinello, B. Cogliati, C. R. Pizzo, et al. (2009). Cytotoxic effects of butanolic extract from Pfaffia paniculata (Brazilian Ginseng) on cultured human breast cancer cell line MCF-7. Experimental and toxicologic pathology 61(1): 75-82.
Najmuddin. S. U. F. S., M. F. Romli, M. Hamid, N. B. Alitheen and N. M. A. N. Abd Rahman (2016). Anti-cancer effect of Annona Muricata Linn Leaves Crude Extract (AMCE) on breast cancer cell line. BMC complementary and alternative medicine 16(1): 1-20.
Park. E. Y., Y. Woo, S. J. Kim, D. H. Kim, E. K. Lee, U. De, K. S. Kim, et al. (2016). Anticancer effects of a new SIRT inhibitor, MHY2256, against human breast cancer MCF-7 cells via regulation of MDM2-p53 binding. International journal of biological sciences 12(12): 1555.
Parker. S. L., T. Tong, S. Bolden and P. A. Wingo (1997). Cancer statistics, 1997. CA: A cancer journal for clinicians 47(1): 5-27.
Portman. N., H. H. Milioli, S. Alexandrou, R. Coulson, A. Yong, K. J. Fernandez, et al. (2020). MDM2 inhibition in combination with endocrine therapy and CDK4/6 inhibition for the treatment of ER-positive breast cancer. Breast Cancer Research 22(1): 1-17.
Proietti. S., A. Cucina, G. Dobrowolny, F. D'Anselmi, S. Dinicola, M. G. Masiello, et al. (2014). Melatonin down‐regulates MDM 2 gene expression and enhances p53 acetylation in MCF‐7 cells. Journal of pineal research 57(1): 120-129.
Qin. J.-J., S. Sarkar, S. Voruganti, R. Agarwal, W. Wang and R. Zhang (2016). Identification of lineariifolianoid A as a novel dual NFAT1 and MDM2 inhibitor for human cancer therapy. Journal of biomedical research 30(4): 322.
Qin. J.-J., W. Wang, S. Sarkar, S. Voruganti, R. Agarwal and R. Zhang (2016). Inulanolide A as a new dual inhibitor of NFAT1-MDM2 pathway for breast cancer therapy. Oncotarget 7(22): 32566.
Qin. J.-J., W. Wang, S. Voruganti, H. Wang, W.-D. Zhang and R. Zhang (2015). Identification of a new class of natural product MDM2 inhibitor: In vitro and in vivo anti-breast cancer activities and target validation. Oncotarget 6(5): 2623.
Qin. J.-J., W. Wang, S. Voruganti, H. Wang, W.-D. Zhang and R. Zhang (2015). Inhibiting NFAT1 for breast cancer therapy: new insights into the mechanism of action of MDM2 inhibitor JapA. Oncotarget 6(32): 33106.
Qin. J.-J., W. Wang and R. Zhang (2017). Experimental therapy of advanced breast cancer: targeting NFAT1–MDM2–p53 pathway. Progress in molecular biology and translational science 151: 195-216.
Raza. S., J. E. Ohm, A. Dhasarathy, J. Schommer, C. Roche, K. D. Hammer et al. (2015). The cholesterol metabolite 27-hydroxycholesterol regulates p53 activity and increases cell proliferation via MDM2 in breast cancer cells. Molecular and cellular biochemistry 410(1): 187-195.
Rong. J.-J., R. Hu, Q. Qi, H.-Y. Gu, Q. Zhao, J. Wang, et al. (2009). Gambogic acid down-regulates MDM2 oncogene and induces p21Waf1/CIP1 expression independent of p53. Cancer letters 284(1): 102-112.
Saji. S., S. Nakashima, S. i. Hayashi, M. Toi, S. Saji and Y. Nozawa (1999). Overexpression of MDM2 in MCF‐7 promotes both growth advantage and p53 accumulation in response to estradiol. Japanese journal of cancer research 90(2): 210-218.
Salahshoor. M. R., M. M. Mohammadi, S. Roshankhah and C. Jalili (2018). Effect of Falcaria Vulgaris on Milk Production Parameters in Female Rats' Mammary Glands. J Family Reprod Health 12(4): 177-183.
Shafaghat. A. (2010). Free radical scavenging and antibacterial activities, and GC/MS analysis of essential oils from different parts of Falcaria vulgaris from two regions. Nat Prod Commun 5(6): 981-984.
Shangary. S., D. Qin, D. McEachern, M. Liu, R. S. Miller, S. Qiu, Z. Nikolovska-Coleska, et al. (2008). Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition. Proceedings of the National Academy of Sciences 105(10): 3933-3938.
Shangary. S. and S. Wang (2009). Small-molecule inhibitors of the MDM2-p53 protein-protein interaction to reactivate p53 function: a novel approach for cancer therapy. Annual review of pharmacology and toxicology 49: 223-241.
Sjöström. J., C. Blomqvist, P. Heikkilä, K. Von Boguslawski, A. Räisänen-Sokolowski, N.-O. Bengtsson, I. Mjaaland, et al. (2000). Predictive value of p53, mdm-2, p21, and mib-1 for chemotherapy response in advanced breast cancer. Clinical cancer research 6(8): 3103-3110.
Soudamani. S., S. Yuvaraj, T. Malini and K. Balasubramanian (2005). Experimental diabetes has adverse effects on the differentiation of ventral prostate during sexual maturation of rats. Anat Rec A Discov Mol Cell Evol Biol 287(2): 1281-1289.
Subash-Babu. P., G. M. Alshammari, S. Ignacimuthu and A. A. Alshatwi (2017). Epoxy clerodane diterpene inhibits MCF-7 human breast cancer cell growth by regulating the expression of the functional apoptotic genes Cdkn2A, Rb1, mdm2 and p53. Biomedicine & Pharmacotherapy 87: 388-396.
Syed Najmuddin. S. U., M. F. Romli, M. Hamid, N. B. Alitheen and N. M. Nik Abd Rahman (2016). Anti-cancer effect of Annona Muricata Linn Leaves Crude Extract (AMCE) on breast cancer cell line. BMC Complement Altern Med 16(1): 311.
Talib. W. H., S. A. Al-Hadid, M. B. W. Ali, I. H. Al-Yasari and M. R. Abd Ali (2018). Role of curcumin in regulating p53 in breast cancer: An overview of the mechanism of action. Breast Cancer: Targets and Therapy 10: 207.
Tovar. C., J. Rosinski, Z. Filipovic, B. Higgins, K. Kolinsky, H. Hilton, et al. (2006). Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proceedings of the National Academy of Sciences 103(6): 1888-1893.
Vassilev. L. T., B. T. Vu, B. Graves, D. Carvajal, F. Podlaski, Z. Filipovic, N. Kong, U. Kammlott, et al. (2004). In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303(5659): 844-848.
Vu. B., P. Wovkulich, G. Pizzolato, A. Lovey, Q. Ding, N. Jiang, J.-J. Liu, et al. (2013). Discovery of RG7112: a small-molecule MDM2 inhibitor in clinical development. ACS medicinal chemistry letters 4(5): 466-469.
Wang. C. H., J. M. Yang, Y. B. Guo, J. Shen and X. H. Pei (2020). Anticancer Activity of Tetrandrine by Inducing Apoptosis in Human Breast Cancer Cell Line MDA-MB-231 In Vivo. Evid Based Complement Alternat Med 2020: 6823520.
Wang. H., X. Ma, S. Ren, J. K. Buolamwini and C. Yan (2011). A small-molecule inhibitor of MDMX activates p53 and induces apoptosis. Molecular cancer therapeutics 10(1): 69-79.
Wang. H. and C. Yan (2011). A small-molecule p53 activator induces apoptosis through inhibiting MDMX expression in breast cancer cells. Neoplasia 13(7): 611-IN616.
Wang. W., E. R. Rayburn, J. Hang, Y. Zhao, H. Wang and R. Zhang (2009). Anti-lung cancer effects of novel ginsenoside 25-OCH3-PPD. Lung Cancer 65(3): 306-311.
Wang. W., E. R. Rayburn, Y. Zhao, H. Wang and R. Zhang (2009). Novel ginsenosides 25-OH-PPD and 25-OCH3-PPD as experimental therapy for pancreatic cancer: anticancer activity and mechanisms of action. Cancer letters 278(2): 241-248.
Wang. W., H. Wang, E. Rayburn, Y. Zhao, D. Hill and R. Zhang (2008). 20 (S)-25-methoxyl-dammarane-3 β, 12 β, 20-triol, a novel natural product for prostate cancer therapy: activity in vitro and in vivo and mechanisms of action. British journal of cancer 98(4): 792-802.
Wiley. C. D., N. Schaum, F. Alimirah, J. A. Lopez-Dominguez, A. V. Orjalo, G. Scott, et al. (2018). Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype. Scientific reports 8(1): 1-9.
Xiong. J., J. Li, Q. Yang, J. Wang, T. Su and S. Zhou (2017). Gossypol has anti-cancer effects by dual-targeting MDM2 and VEGF in human breast cancer. Breast Cancer Research 19(1): 1-10.
Xiong. J., T. Su, Z. Qu, Q. Yang, Y. Wang, J. Li and S. Zhou (2016). Triptolide has anticancer and chemosensitization effects by down-regulating Akt activation through the MDM2/REST pathway in human breast cancer. Oncotarget 7(17): 23933.
Xu. Y. (2008). Induction of genetic instability by gain-of-function p53 cancer mutants. Oncogene 27(25): 3501-3507.
Zawacka‐Pankau. J. and G. Selivanova (2015). Pharmacological reactivation of p53 as a strategy to treat cancer. Journal of internal medicine 277(2): 248-259.
Zhou. R., H. Chen, J. Chen, X. Chen, Y. Wen and L. Xu (2018). Extract from Astragalus membranaceus inhibit breast cancer cells proliferation via PI3K/AKT/mTOR signaling pathway. BMC complementary and alternative medicine 18(1): 1-8.