Abstract
Background: Cancer metastasis has emerged as a major public health threat that causes majority of cancer fatalities. Traditional chemotherapeutics have been effective in the past but suffer from low therapeutic efficiency and harmful side-effects. Recently, it has been reported ursolic acid (UA), one of the naturally abundant pentacyclic triterpenes, possesses a wide range of biological activities including anti-inflammatory, anti-atherosclerotic, and anti-cancer properties. More importantly, UA has the features of low toxicity, liver protection and the potential of anti-cancer metastasis.
Objective: This article aimed at reviewing the great potential of UA used as a candidate drug in the field of cancer therapy relating to suppression of tumor initiation, progression and metastasis.
Methods: Selective searches were conducted in Pubmed, Google Scholar and Web of Science using the keywords and subheadings from database inception to December 2017. Systemic reviews are summarized here.
Results: UA has exhibited chemopreventive and therapeutic effects of cancer mainly through inducing apoptosis, inhibiting cell proliferation, preventing tumor angiogenesis and metastatic. UA nanoformulations could enhance the solubility and bioavailability of UA as well as exhibit better inhibitory effect on tumor growth and metastasis.
Conclusion: The information presented in this article can provide useful references for further studies on making UA a promising anti-cancer drug, especially as a prophylactic metastatic agent for clinical applications.
Keywords: Ursolic acid, cancer metastasis, chemoprevention, mechanisms, UA derivatives, UA nanoformulations.
Graphical Abstract
[1]
Ferlay, J.; Shin, H.R.; Bray, F.; Forman, D.; Mathers, C.; Parkin, D.M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer, 2010, 127(12), 2893-2917.
[2]
DeSantis, C.E.; Lin, C.C.; Mariotto, A.B.; Siegel, R.L.; Stein, K.D.; Kramer, J.L.; Alteri, R.; Robbins, A.S.; Jemal, A. Cancer treatment and survivorship statistics, 2014. CA Cancer J. Clin., 2014, 64(4), 252-271.
[3]
Shanmugam, M.K.; Nguyen, A.H.; Kumar, A.P.; Tan, B.K.H.; Sethi, G. Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer. Cancer Lett., 2012, 320(2), 158-170.
[4]
Zhang, J.; Li, Y.; Chen, S.S.; Zhang, L.; Wang, J.; Yang, Y.; Zhang, S.; Pan, Y.; Wang, Y.; Yang, L. Systems pharmacology dissection of the anti-inflammatory mechanism for the medicinal herb Folium eriobotryae. Int. J. Mol. Sci., 2015, 16(2), 2913-2941.
[5]
Chen, H.; Yang, J.; Zhang, Q.; Chen, L.H.; Wang, Q. Corosolic acid ameliorates atherosclerosis in apolipoprotein E-deficient mice by regulating the nuclear factor-kappaB signaling pathway and inhibiting monocyte chemoattractant protein-1 expression. Circ. J., 2012, 76(4), 995-1003.
[6]
Wei, J.; Liu, M.; Liu, H.; Wang, H.; Wang, F.; Zhang, Y.; Han, L.; Lin, X. Oleanolic acid arrests cell cycle and induces apoptosis via ROS-mediated mitochondrial depolarization and lysosomal membrane permeabilization in human pancreatic cancer cells. J. Appl. Toxicol., 2013, 33(8), 756-765.
[7]
(a) Juan, M.E.; Planas, J.M.; Ruiz-Gutierrez, V.; Daniel, H.; Wenzel, U. Antiproliferative and apoptosis-inducing effects of maslinic and oleanolic acids, two pentacyclic triterpenes from olives, on HT-29 colon cancer cells. Br. J. Nutr., 2008, 100(1), 36-43.
(b) Li, J.; Guo, W.J.; Yang, Q.Y. Effects of ursolic acid and oleanolic acid on human colon carcinoma cell line HCT15. World J. Gastroenterol., 2002, 8(3), 493-495.
(b) Li, J.; Guo, W.J.; Yang, Q.Y. Effects of ursolic acid and oleanolic acid on human colon carcinoma cell line HCT15. World J. Gastroenterol., 2002, 8(3), 493-495.
[8]
Li, J.; Guo, W.J.; Yang, Q.Y. Effects of ursolic acid and oleanolic acid on human colon carcinoma cell line HCT15. World J. Gastroenterol., 2002, 8(3), 493-495.
[9]
(a) Bishayee, A.; Ahmed, S.; Brankov, N.; Perloff, M. Triterpenoids as potential agents for the chemoprevention and therapy of breast cancer. Front. Biosci., 2011, 16, 980-996.
(b) Allouche, Y.; Warleta, F.; Campos, M.; Sanchez-Quesada, C.; Uceda, M.; Beltran, G.; Gaforio, J.J. Antioxidant, antiproliferative, and pro-apoptotic capacities of pentacyclic triterpenes found in the skin of olives on MCF-7 human breast cancer cells and their effects on DNA damage. J. Agric. Food Chem., 2011, 59(1), 121-130.
(b) Allouche, Y.; Warleta, F.; Campos, M.; Sanchez-Quesada, C.; Uceda, M.; Beltran, G.; Gaforio, J.J. Antioxidant, antiproliferative, and pro-apoptotic capacities of pentacyclic triterpenes found in the skin of olives on MCF-7 human breast cancer cells and their effects on DNA damage. J. Agric. Food Chem., 2011, 59(1), 121-130.
[10]
Allouche, Y.; Warleta, F.; Campos, M.; Sanchez-Quesada, C.; Uceda, M.; Beltran, G.; Gaforio, J.J. Antioxidant, antiproliferative, and pro-apoptotic capacities of pentacyclic triterpenes found in the skin of olives on MCF-7 human breast cancer cells and their effects on DNA damage. J. Agric. Food Chem., 2011, 59(1), 121-130.
[11]
He, X.J.; Liu, R.H. Triterpenoids isolated from apple peels have potent antiproliferative activity and may be partially responsible for apple’s anticancer activity. J. Agric. Food Chem., 2007, 55(11), 4366-4370.
[12]
Kassi, E.; Papoutsi, Z.; Pratsinis, H.; Aligiannis, N.; Manoussakis, M.; Moutsatsou, P. Ursolic acid, a naturally occurring triterpenoid, demonstrates anticancer activity on human prostate cancer cells. J. Cancer Res. Clin., 2007, 133(7), 493-500.
[13]
Harikumar, K.B.; Sung, B.; Pandey, M.K.; Guha, S.; Krishnan, S.; Aggarwal, B.B. Escin, a pentacyclic triterpene, chemosensitizes human tumor cells through inhibition of nuclear factor-kappa B signaling pathway. Mol. Pharmacol., 2010, 77(5), 818-827.
[14]
(a) Janicsák, G.; Veres, K.; Zoltán Kakasy, A.; Máthé, I. Study of the oleanolic and ursolic acid contents of some species of the Lamiaceae. Biochem. Syst. Ecol., 2006, 34(5), 392-396.
(b) Silva, M.G.; Vieira, I.G.; Mendes, F.N.; Albuquerque, I.L.; dos Santos, R.N.; Silva, F.O.; Morais, S.M. Variation of ursolic acid content in eight Ocimum species from northeastern Brazil. Molecules, 2008, 13(10), 2482-2487.
(b) Silva, M.G.; Vieira, I.G.; Mendes, F.N.; Albuquerque, I.L.; dos Santos, R.N.; Silva, F.O.; Morais, S.M. Variation of ursolic acid content in eight Ocimum species from northeastern Brazil. Molecules, 2008, 13(10), 2482-2487.
[15]
Silva, M.G.V.; Vieira, I.G.P.; Mendes, F.N.P.; Albuquerque, I.L.; dos Santos, R.N.; Silva, F.O.; Morais, S.M. Variation of ursolic acid content in eight Ocimum species from northeastern Brazil. Molecules, 2008, 13(10), 2482-2487.
[16]
Ngo, S.N.T.; Williams, D.B.; Head, R.J. Rosemary and cancer prevention: Preclinical perspectives. Crit. Rev. Food Sci. , 2011, 51(10), 946-954.
[17]
Wang, Z.H.; Hsu, C.C.; Huang, C.N.; Yin, M.C. Anti-glycative effects of oleanolic acid and ursolic acid in kidney of diabetic mice. Eur. J. Pharmacol., 2010, 628(1-3), 255-260.
[18]
Ohigashi, H.; Takamura, H.; Koshimizu, K.; Tokuda, H.; Ito, Y. Search for possible antitumor promoters by inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced Epstein-Barr virus activation; ursolic acid and oleanolic acid from an anti-inflammatory Chinese medicinal plant, Glechoma hederaceae L. Cancer Lett., 1986, 30(2), 143-151.
[19]
Andersson, D.; Liu, J.J.; Nilsson, A.; Duan, R.D. Ursolic acid inhibits proliferation and stimulates apoptosis in HT29 cells following activation of alkaline sphingomyelinase. Anticancer Res., 2003, 23(4), 3317-3322.
[20]
(a) Wang, J.; Liu, L.; Qiu, H.; Zhang, X.; Guo, W.; Chen, W.; Tian, Y.; Fu, L.; Shi, D.; Cheng, J.; Huang, W.; Deng, W. Ursolic acid simultaneously targets multiple signaling pathways to suppress proliferation and induce apoptosis in colon cancer cells. PLoS One, 2013, 8(5), e63872.
(b) Shan, J.Z.; Xuan, Y.Y.; Zhang, Q.; Huang, J.J. Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1 alpha. J. Zhejiang Univ. Sci. B, 2016, 17(9), 672-682.
(b) Shan, J.Z.; Xuan, Y.Y.; Zhang, Q.; Huang, J.J. Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1 alpha. J. Zhejiang Univ. Sci. B, 2016, 17(9), 672-682.
[21]
Shan, J.Z.; Xuan, Y.Y.; Zhang, Q.; Huang, J.J. Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1 alpha. J. Zhejiang Univ. Sci. B, 2016, 17(9), 672-682.
[22]
(a) Jin, H.; Pi, J.; Yang, F.; Jiang, J.; Wang, X.; Bai, H.; Shao, M.; Huang, L.; Zhu, H.; Yang, P.; Li, L.; Li, T.; Cai, J.; Chen, Z.W. Folate-chitosan nanoparticles loaded with ursolic acid confer anti-breast cancer activities in vitro and in vivo. Sci. Rep., 2016, 6, 30782.
(b) Yeh, C.T.; Wu, C.H.; Yen, G.C. Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c-Jun N-terminal kinase, Akt and mammalian target of rapamycin signaling. Mol. Nutr. Food Res., 2010, 54(9), 1285-1295.
(b) Yeh, C.T.; Wu, C.H.; Yen, G.C. Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c-Jun N-terminal kinase, Akt and mammalian target of rapamycin signaling. Mol. Nutr. Food Res., 2010, 54(9), 1285-1295.
[23]
Yeh, C.T. Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c-Jun N-terminal kinase, Akt and mammalian target of rapamycin signaling. Mol. Nutr. Food Res., 2010, 54(11), 1696-1696.
[24]
(a) Zhang, H.; Zheng, D.H.; Ding, J.; Xu, H.E.; Li, X.L.; Sun, W.H. Efficient delivery of ursolic acid by poly(N-vinylpyrrolidone)-block-poly (epsilon-caprolactone) nanoparticles for inhibiting the growth of hepatocellular carcinoma in vitro and in vivo. Int. J. Nanomedicine, 2015, 10, 1909-1920.
(b) Gayathri, R.; Priya, D.K.; Gunassekaran, G.R.; Sakthisekaran, D. Ursolic acid attenuates oxidative stress-mediated hepatocellular carcinoma induction by diethylnitrosamine in male Wistar rats. Asian Pac. J. Cancer Prev., 2009, 10(5), 933-938.
(b) Gayathri, R.; Priya, D.K.; Gunassekaran, G.R.; Sakthisekaran, D. Ursolic acid attenuates oxidative stress-mediated hepatocellular carcinoma induction by diethylnitrosamine in male Wistar rats. Asian Pac. J. Cancer Prev., 2009, 10(5), 933-938.
[25]
Gayathri, R.; Priya, D.K.D.; Gunassekaran, G.R.; Sakthisekaran, D. Ursolic acid attenuates oxidative stress-mediated hepatocellular carcinoma induction by diethylnitrosamine in male wistar rats. Asian Pac. J. Cancer Prev., 2009, 10(5), 933-938.
[26]
Shanmugam, M.K.; Ong, T.H.; Kumar, A.P.; Lun, C.K.; Ho, P.C.; Wong, P.T.; Hui, K.M.; Sethi, G. Ursolic acid inhibits the initiation, progression of prostate cancer and prolongs the survival of TRAMP mice by modulating pro-inflammatory pathways. PLoS One, 2012, 7(3), e32476.
[27]
Gao, N.; Cheng, S.P.; Budhraja, A.; Gao, Z.Y.; Chen, J.P.; Liu, E.H.; Huang, C.; Chen, D.Y.; Yang, Z.L.; Liu, Q.; Li, P.; Shi, X.L.; Zhang, Z. Ursolic acid induces apoptosis in human leukaemia cells and exhibits anti-leukaemic activity in nude mice through the PKB pathway. Br. J. Pharmacol., 2012, 165(6), 1813-1826.
[28]
Du, H.; Chen, X.Q. CD-MEKC method to analyze triterpene acids in traditional chinese medicines. J. Braz. Chem. Soc., 2009, 20(7), 1268-1274.
[29]
Liu, H. Oleanolic acid and ursolic acid: Research perspectives. J. Ethnopharmacol., 2005, 100(1-2), 92-94.
[30]
Maulvi, F.A.; Dalwadi, S.J.; Thakkar, V.T.; Soni, T.G.; Gohel, M.C.; Gandhi, T.R. Improvement of dissolution rate of aceclofenac by solid dispersion technique. Powder Technol., 2011, 207(1-3), 47-54.
[31]
Hsu, Y.L.; Kuo, P.L.; Lin, C.C. Proliferative inhibition, cell-cycle dysregulation, and induction of apoptosis by ursolic acid in human non-small cell lung cancer A549 cells. Life Sci., 2004, 75(19), 2303-2316.
[32]
van Horssen, R.; ten Hagen, T.L.M.; Eggermont, A.M.M. TNF-alpha in cancer treatment: Molecular insights, antitumor effects, and clinical utility. Oncologist, 2006, 11(4), 397-408.
[33]
Tamm, I.; Wang, Y.; Sausville, E.; Scudiero, D.A.; Vigna, N.; Oltersdorf, T.; Reed, J.C. IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res., 1998, 58(23), 5315-5320.
[34]
Curtin, N.J.; Szabo, C. Therapeutic applications of PARP inhibitors: anticancer therapy and beyond. Mol. Aspects Med., 2013, 34(6), 1217-1256.
[35]
(a) Zhang, Y.X.; Kong, C.Z.; Wang, L.H.; Li, J.Y.; Liu, X.K.; Xu, B.; Xu, C.L.; Sun, Y.H. Ursolic acid overcomes Bcl-2-mediated resistance to apoptosis in prostate cancer cells involving activation of JNK-induced Bcl-2 phosphorylation and degradation. J. Cell. Biochem., 2010, 109(4), 764-773.
(b) Park, J.H.; Kwon, H.Y.; Sohn, E.J.; Kim, K.A.; Kim, B.; Jeong, S.J.; Song, J.H.; Koo, J.S.; Kim, S.H. Inhibition of Wnt/beta-catenin signaling mediates ursolic acid-induced apoptosis in PC-3 prostate cancer cells. Pharmacol. Rep., 2013, 65(5), 1366-1374.
(b) Park, J.H.; Kwon, H.Y.; Sohn, E.J.; Kim, K.A.; Kim, B.; Jeong, S.J.; Song, J.H.; Koo, J.S.; Kim, S.H. Inhibition of Wnt/beta-catenin signaling mediates ursolic acid-induced apoptosis in PC-3 prostate cancer cells. Pharmacol. Rep., 2013, 65(5), 1366-1374.
[36]
Park, J.H.; Kwon, H.Y.; Sohn, E.J.; Kim, K.A.; Kim, B.; Jeong, S.J.; Song, J.H.; Koo, J.S.; Kim, S.H. Inhibition of Wnt/beta-catenin signaling mediates ursolic acid-induced apoptosis in PC-3 prostate cancer cells. Pharmacol. Rep., 2013, 65(5), 1366-1374.
[37]
Hsu, Y.L.; Kuo, P.L.; Lin, C.C. Proliferative inhibition, cell-cycle dysregulation, and induction of apoptosis by ursolic acid in human non-small cell lung cancer A549 cells. Life Sci., 2004, 75(19), 2303-2316.
[38]
(a) Li, Y.; Xing, D.; Chen, Q.; Chen, W.R. Enhancement of chemotherapeutic agent-induced apoptosis by inhibition of NF-kappaB using ursolic acid. Int. J. Cancer, 2010, 127(2), 462-473.
(b) Manu, K.A.; Kuttan, G. Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-kappaB mediated activation of bcl-2 in B16F-10 melanoma cells. Int. Immunopharmacol., 2008, 8(7), 974-981.
(c) Gao, X.; Deeb, D.; Jiang, H.; Liu, Y.; Dulchavsky, S.A.; Gautam, S.C. Synthetic triterpenoids inhibit growth and induce apoptosis in human glioblastoma and neuroblastoma cells through inhibition of prosurvival Akt, NF-kappaB and Notch1 signaling. J. Neurooncol., 2007, 84(2), 147-157.
(b) Manu, K.A.; Kuttan, G. Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-kappaB mediated activation of bcl-2 in B16F-10 melanoma cells. Int. Immunopharmacol., 2008, 8(7), 974-981.
(c) Gao, X.; Deeb, D.; Jiang, H.; Liu, Y.; Dulchavsky, S.A.; Gautam, S.C. Synthetic triterpenoids inhibit growth and induce apoptosis in human glioblastoma and neuroblastoma cells through inhibition of prosurvival Akt, NF-kappaB and Notch1 signaling. J. Neurooncol., 2007, 84(2), 147-157.
[39]
Manu, K.A.; Kuttan, G. Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-kappa B mediated activation of bcl-2 in B16F-10 melanoma cells. Int. Immunopharmacol., 2008, 8(7), 974-981.
[40]
Gao, X.; Deeb, D.; Jiang, H.; Liu, Y.; Dulchavsky, S.A.; Gautam, S.C. Synthetic triterpenoids inhibit growth and induce apoptosis in human glioblastoma and neuroblastoma cells through inhibition of prosurvival Akt, NF-kappa B and Notch1 signaling. J. Neurooncol., 2007, 84, 147-157.
[41]
Limami, Y.; Pinon, A.; Leger, D.Y.; Mousseau, Y.; Cook-Moreau, J.; Beneytout, J.L.; Delage, C.; Liagre, B.; Simon, A. HT-29 colorectal cancer cells undergoing apoptosis overexpress COX-2 to delay ursolic acid-induced cell death. Biochimie, 2011, 93(4), 749-757.
[42]
Achiwa, Y.; Hasegawa, K.; Udagawa, Y. Regulation of the phosphatidylinositol 3-kinase-Akt and the mitogen-activated protein kinase pathways by ursolic acid in human endometrial cancer cells. Biosci. Biotechnol. Biochem., 2007, 71(1), 31-37.
[43]
Pathak, A.K.; Bhutani, M.; Nair, A.S.; Ahn, K.S.; Chakraborty, A.; Kadara, H.; Guha, S.; Sethi, G.; Aggarwal, B.B. Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol. Cancer Res., 2007, 5(9), 943-955.
[44]
Prasad, S.; Yadav, V.R.; Kannappan, R.; Aggarwal, B.B. Ursolic acid, a pentacyclin triterpene, potentiates TRAIL-induced apoptosis through p53-independent up-regulation of death receptors (Retraction of vol 286, pg 5546, 2011). J. Biol. Chem., 2016, 291(32), 16924-16924.
[45]
Lauthier, F.; Taillet, L.; Trouillas, P.; Delage, C.; Simon, A. Ursolic acid triggers calcium-dependent apoptosis in human Daudi cells. Anticancer Drugs, 2000, 11(9), 737-745.
[46]
Tu, H.Y.; Huang, A.M.; Wei, B.L.; Gan, K.H.; Hour, T.C.; Yang, S.C.; Pu, Y.S.; Lin, C.N. Ursolic acid derivatives induce cell cycle arrest and apoptosis in NTUB1 cells associated with reactive oxygen species. Bioorg. Med. Chem., 2009, 17(20), 7265-7274.
[47]
Liu, X.S.; Jiang, J.K. Induction of apoptosis and regulation of the MAPK pathway by ursolic acid in human leukemia K562 cells. Planta Med., 2007, 73(11), 1192-1194.
[48]
Zhang, Y.X.; Kong, C.Z.; Wang, L.H.; Li, J.Y.; Liu, X.K.; Xu, B.; Xu, C.L.; Sun, Y.H. Ursolic acid overcomes Bcl-2-mediated resistance to apoptosis in prostate cancer cells involving activation of JNK-Induced Bcl-2 phosphorylation and degradation. J. Cell. Biochem., 2010, 109(4), 764-773.
[49]
Gao, N.; Cheng, S.P.; Budhraja, A.; Gao, Z.Y.; Chen, J.P.; Liu, E.H.; Huang, C.; Chen, D.Y.; Yang, Z.L.; Liu, Q.; Li, P.; Shi, X.L.; Zhang, Z. Ursolic acid induces apoptosis in human leukaemia cells and exhibits anti-leukaemic activity in nude mice through the PKB pathway. Br. J. Pharmacol., 2012, 165(6), 1813-1826.
[50]
Liu, X.S.; Jiang, J.K. Induction of apoptosis and regulation of the MAPK pathway by ursolic acid in human leukemia K562 cells. Planta Med., 2007, 73(11), 1192-1194.
[51]
Manu, K.A.; Kuttan, G. Ursolic acid induces apoptosis by activating p53 and caspase-3 gene expressions and suppressing NF-kappaB mediated activation of bcl-2 in B16F-10 melanoma cells. Int. Immunopharmacol., 2008, 8(7), 974-981.
[52]
Achiwa, Y.; Hasegawa, K.; Udagawa, Y. Regulation of the phosphatidylinositol 3-kinase-Akt and the mitogen-activated protein kinase pathways by ursolic acid in human endometrial cancer cells. Biosci. Biotechnol. Biochem., 2007, 71(1), 31-37.
[54]
Kiran, M.S.; Viji, R.I.; Sameer Kumar, V.B.; Sudhakaran, P.R. Modulation of angiogenic factors by ursolic acid. Biochem. Biophys. Res. Commun., 2008, 371(3), 556-560.
[55]
Kanjoormana, M.; Kuttan, G. Antiangiogenic activity of ursolic acid. Integr. Cancer Ther., 2010, 9(2), 224-235.
[56]
Das, B.; Yeger, H.; Tsuchida, R.; Torkin, R.; Gee, M.F.W.; Thorner, P.S.; Shibuya, M.; Malkin, D.; Baruchel, S. A hypoxia-driven vascular endothelial growth factor/Flt1 autocrine loop interacts with hypoxia-inducible factor-1 alpha through mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 pathway in neuroblastoma. Cancer Res., 2005, 65(16), 7267-7275.
[58]
Wan, L.L.; Pantel, K.; Kang, Y.B. Tumor metastasis: moving new biological insights into the clinic. Nat. Med., 2013, 19(11), 1450-1464.
[59]
Hamano, Y.; Zeisberg, M.; Sugimoto, H.; Lively, J.C.; Maeshima, Y.; Yang, C.; Hynes, R.O.; Werb, Z.; Sudhakar, A.; Kalluri, R. Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrin. Cancer Cell, 2003, 3(6), 589-601.
[60]
Pritchard, S.C.; Nicolson, M.C.; Lloret, C.; McKay, J.A.; Ross, V.G.; Kerr, K.M.; Murray, G.I.; McLeod, H.L. Expression of matrix metalloproteinases 1, 2, 9 and their tissue inhibitors in stage II non-small cell lung cancer: Implications for MMP inhibition therapy. Oncol. Rep., 2001, 8(2), 421-424.
[61]
Guo, C.B.; Wang, S.; Deng, C.; Zhang, D.L.; Wang, F.L.; Jin, X.Q. Relationship between matrix metalloproteinase 2 and lung cancer progression. Mol. Diagn. Ther., 2007, 11(3), 183-192.
[62]
Hung, W.C.; Tseng, W.L.; Shiea, J.; Chang, H.C. Skp2 overexpression increases the expression of MMP-2 and MMP-9 and invasion of lung cancer cells. Cancer Lett., 2010, 288(2), 156-161.
[63]
Insug, O.; Otvos, Jr L.; Kieber-Emmons, T.; Blaszczyk-Thurin, M. Role of SA-Le(a) and E-selectin in metastasis assessed with peptide antagonist. Peptides, 2002, 23(5), 999-1010.
[64]
Xiang, L.P.; Chi, T.; Tang, Q.; Yang, X.; Ou, M.R.; Chen, X.F.; Yu, X.B.; Chen, J.Z.; Ho, R.J.Y.; Shao, J.W.; Jia, L. A pentacyclic triterpene natural product, ursolic acid and its prodrug US597 inhibit targets within cell adhesion pathway and prevent cancer metastasis. Oncotarget, 2015, 6(11), 9295-9312.
[65]
Huang, C.Y.; Lin, C.Y.; Tsai, C.W.; Yin, M.C. Inhibition of cell proliferation, invasion and migration by ursolic acid in human lung cancer cell lines. Toxicol. In Vitro, 2011, 25(7), 1274-1280.
[66]
Shishodia, S.; Majumdar, S.; Banerjee, S.; Aggarwal, B.B. Ursolic acid inhibits nuclear factor-kappa B activation induced by carcinogenic agents through suppression of I kappa B alpha kinase and p65 phosphorylation: Correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res., 2003, 63(15), 4375-4383.
[67]
Yim, E.K.; Lee, M.J.; Lee, K.H.; Um, S.J.; Park, J.S. Antiproliferative and antiviral mechanisms of ursolic acid and dexamethasone in cervical carcinoma cell lines. Int. J. Gynecol. Cancer, 2006, 16(6), 2023-2031.
[68]
Prasad, S.; Yadav, V.R.; Sung, B.; Gupta, S.C.; Tyagi, A.K.; Aggarwal, B.B. Ursolic acid inhibits the growth of human pancreatic cancer and enhances the antitumor potential of gemcitabine in an orthotopic mouse model through suppression of the inflammatory microenvironment. Oncotarget, 2016, 7(11), 13182-13196.
[69]
Caldeira de Araujo Lopes, S.; Vinicius Melo Novais, M.; Salviano Teixeira, C.; Honorato-Sampaio, K.; Tadeu Pereira, M.; Ferreira, L.A.; Braga, F.C.; Cristina Oliveira, M. Preparation, physicochemical characterization, and cell viability evaluation of long-circulating and pH-sensitive liposomes containing ursolic acid. BioMed Res. Int., 2013, 2013, 467147.
[70]
Meng, Y.Q.; Liu, D.; Cai, L.L.; Chen, H.; Cao, B.; Wang, Y.Z. The synthesis of ursolic acid derivatives with cytotoxic activity and the investigation of their preliminary mechanism of action. Bioorg. Med. Chem., 2009, 17(2), 848-854.
[71]
Chadalapaka, G.; Jutooru, I.; McAlees, A.; Stefanac, T.; Safe, S. Structure-dependent inhibition of bladder and pancreatic cancer cell growth by 2-substituted glycyrrhetinic and ursolic acid derivatives. Bioorg. Med. Chem. Lett., 2008, 18(8), 2633-2639.
[72]
(a) Chen, L.; Qiu, W.; Tang, J.; Wang, Z.F.; He, S.Y. Synthesis and bioactivity of novel nitric oxide-releasing ursolic acid derivatives. Chin. Chem. Lett., 2011, 22(4), 413-416.
(b) Meng, Y-Q.; Liu, D.; Cai, L-L.; Chen, H.; Cao, B.; Wang, Y-Z. The synthesis of ursolic acid derivatives with cytotoxic activity and the investigation of their preliminary mechanism of action. Bioorg. Med. Chem., 2009, 17(2), 848-854.
(b) Meng, Y-Q.; Liu, D.; Cai, L-L.; Chen, H.; Cao, B.; Wang, Y-Z. The synthesis of ursolic acid derivatives with cytotoxic activity and the investigation of their preliminary mechanism of action. Bioorg. Med. Chem., 2009, 17(2), 848-854.
[73]
Ma, C.M.; Cai, S.Q.; Cui, J.R.; Wang, R.Q.; Tu, P.F.; Hattori, M.; Daneshtalab, M. The cytotoxic activity of ursolic acid derivatives. Eur. J. Med. Chem., 2005, 40(6), 582-589.
[74]
Tu, H-Y.; Huang, A.M.; Wei, B-L.; Gan, K-H.; Hour, T-C.; Yang, S-C.; Pu, Y-S.; Lin, C-N. Ursolic acid derivatives induce cell cycle arrest and apoptosis in NTUB1 cells associated with reactive oxygen species. Bioorg. Med. Chem., 2009, 17(20), 7265-7274.
[75]
Meng, Y.Q.; Cao, J.; Tang, Y.; Lu, X.Y.; Liu, L.W. Synthesis and anti-tumor activity of derivatives of ring a of ursolic acid. Chinese J. Org. Chem., 2016, 36(5), 1080-1087.
[76]
Liu, D.; Meng, Y.Q.; Zhao, J.; Chen, L.G. Synthesis and anti-tumor activity of novel amide derivatives of ursolic acid. Chem. Res. Chin. Univ., 2008, 24(1), 42-46.
[77]
Liu, M.C.; Yang, S.J.; Jin, L.H.; Hu, D.Y.; Xue, W.; Song, B.A.; Yang, S. Synthesis and cytotoxicity of novel ursolic acid derivatives containing an acyl piperazine moiety. Eur. J. Med. Chem., 2012, 58, 128-135.
[78]
Bai, K.K.; Yu, Z.; Chen, F.L.; Li, F.; Li, W.Y.; Guo, Y.H. Synthesis and evaluation of ursolic acid derivatives as potent cytotoxic agents. Bioorg. Med. Chem. Lett., 2012, 22(7), 2488-2493.
[79]
Wang, J.C.; Jiang, Z.; Xiang, L.P.; Li, Y.F.; Ou, M.R.; Yang, X.; Shao, J.W.; Lu, Y.S.; Lin, L.F.; Chen, J.Z.; Dai, Y.; Jia, L. Synergism of ursolic acid derivative US597 with 2-deoxy-D-glucose to preferentially induce tumor cell death by dual-targeting of apoptosis and glycolysis. Sci. Rep-UK, 2014, 4, 5006.
[80]
Dong, H.; Yang, X.; Xie, J.; Xiang, L.; Li, Y.; Ou, M.; Chi, T.; Liu, Z.; Yu, S.; Gao, Y.; Chen, J.; Shao, J.; Jia, L. UP12, a novel ursolic acid derivative with potential for targeting multiple signaling pathways in hepatocellular carcinoma. Biochem. Pharmacol., 2015, 93(2), 151-162.
[81]
Liu, D.; Meng, Y.Q.; Zhao, J.; Chen, L.G. Synthesis and anti-tumor activity of novel amide derivatives of ursolic acid. Chem. Res. Chin. Univ., 2008, 24(1), 42-46.
[82]
Shao, J.W.; Dai, Y.C.; Xue, J.P.; Wang, J.C.; Lin, F.P.; Guo, Y.H. In vitro and In vivo anticancer activity evaluation of ursolic acid derivatives. Eur. J. Med. Chem., 2011, 46(7), 2652-2661.
[83]
Mendes, V.I.; Bartholomeusz, G.A.; Ayres, M.; Gandhi, V.; Salvador, J.A. Synthesis and cytotoxic activity of novel A-ring cleaved ursolic acid derivatives in human non-small cell lung cancer cells. Eur. J. Med. Chem., 2016, 123, 317-331.
[84]
Fu, S.B.; Yang, J.S.; Cui, J.L.; Feng, X.; Sun, D.A. Biotransformation of ursolic acid by an endophytic fungus from medicinal plant Huperzia serrata. Chem. Pharm. Bull. , 2011, 59(9), 1180-1182.
[85]
Tang, Q.; Liu, Y.; Li, T.; Yang, X.; Zheng, G.; Chen, H.; Jia, L.; Shao, J. A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: multiple targets for cancer metastasis prevention and treatment. Oncotarget, 2016, 7(45), 73114-73129.
[86]
Yoon, Y.; Lim, J.W.; Kim, J.; Kim, Y.; Chun, K.H. Discovery of ursolic acid prodrug (NX-201): Pharmacokinetics and in vivo antitumor effects in PANC-1 pancreatic cancer. Bioorg. Med. Chem. Lett., 2016, 26(22), 5524-5527.
[87]
Jorgensen, W.L. The many roles of computation in drug discovery. Science, 2004, 303(5665), 1813-1818.
[88]
Clark, L.A.; Boriack-Sjodin, P.A.; Eldredge, J.; Fitch, C.; Friedman, B.; Hanf, K.J.M.; Jarpe, M.; Liparoto, S.F.; Li, Y.; Lugovskoy, A.; Miller, S.; Rushe, M.; Sherman, W.; Simon, K.; Van Vlijmen, H. Affinity enhancement of an in vivo matured therapeutic antibody using structure-based computational design. Protein Sci., 2006, 15(5), 949-960.
[89]
Cong, X.; Topin, J.; Golebiowski, J.; Class, A. GPCRs: Structure, function, modeling and structure-based ligand design. Curr. Pharm. Des., 2017, 23(29), 4390-4409.
[90]
Xiang, L.; Chi, T.; Tang, Q.; Yang, X.; Ou, M.; Chen, X.; Yu, X.; Chen, J.; Ho, R.J.; Shao, J.; Jia, L. A pentacyclic triterpene natural product, ursolic acid and its prodrug US597 inhibit targets within cell adhesion pathway and prevent cancer metastasis. Oncotarget, 2015, 6(11), 9295-9312.
[91]
(a) Baek, S.; Singh, R.K.; Khanal, D.; Patel, K.D.; Lee, E.J.; Leong, K.W.; Chrzanowski, W.; Kim, H.W. Smart multifunctional drug delivery towards anticancer therapy harmonized in mesoporous nanoparticles. Nanoscale, 2015, 7(34), 14191-14216.
(b) Chan, J.M.; Zhang, L.; Yuet, K.P.; Liao, G.; Rhee, J.W.; Langer, R.; Farokhzad, O.C. PLGA-lecithin-PEG core-shell nanoparticles for controlled drug delivery. Biomaterials, 2009, 30(8), 1627-1634.
(b) Chan, J.M.; Zhang, L.; Yuet, K.P.; Liao, G.; Rhee, J.W.; Langer, R.; Farokhzad, O.C. PLGA-lecithin-PEG core-shell nanoparticles for controlled drug delivery. Biomaterials, 2009, 30(8), 1627-1634.
[92]
Chan, J.M.; Zhang, L.F.; Yuet, K.P.; Liao, G.; Rhee, J.W.; Langer, R.; Farokhzad, O.C. PLGA-lecithin-PEG core-shell nanoparticles for controlled drug delivery. Biomaterials, 2009, 30(8), 1627-1634.
[93]
Kraft, J.C.; Freeling, J.P.; Wang, Z.; Ho, R.J. Emerging research and clinical development trends of liposome and lipid nanoparticle drug delivery systems. J. Pharm. Sci., 2014, 103(1), 29-52.
[94]
Wilson, B.; Samanta, M.K.; Santhi, K.; Kumar, K.P.; Ramasamy, M.; Suresh, B. Chitosan nanoparticles as a new delivery system for the anti-Alzheimer drug tacrine. Nanotechnol. Biol. Med., 2010, 6(1), 144-152.
[95]
(a) Zentner, G.M.; Rathi, R.; Shih, C.; McRea, J.C.; Seo, M.H.; Oh, H.; Rhee, B.G.; Mestecky, J.; Moldoveanu, Z.; Morgan, M.; Weitman, S. Biodegradable block copolymers for delivery of proteins and water-insoluble drugs. J. Control. Release, 2001, 72(1-3), 203-215.
(b) Chen, S.; Pieper, R.; Webster, D.C.; Singh, J. Triblock copolymers: synthesis, characterization, and delivery of a model protein. Int. J. Pharm., 2005, 288(2), 207-218.
(b) Chen, S.; Pieper, R.; Webster, D.C.; Singh, J. Triblock copolymers: synthesis, characterization, and delivery of a model protein. Int. J. Pharm., 2005, 288(2), 207-218.
[96]
Chen, S.B.; Pieper, R.; Webster, D.C.; Singh, J. Triblock copolymers: synthesis, characterization, and delivery of a model protein. Int. J. Pharm., 2005, 288(2), 207-218.
[97]
Chen, C.; Geng, J.; Pu, F.; Yang, X.; Ren, J.; Qu, X. Polyvalent nucleic acid/mesoporous silica nanoparticle conjugates: dual stimuli-responsive vehicles for intracellular drug delivery. Angew. Chem., 2011, 50(4), 882-886.
[98]
Zhang, X.; Li, N.; Liu, Y.; Ji, B.; Wang, Q.; Wang, M.; Dai, K.; Gao, D. On-demand drug release of ICG-liposomal wedelolactone combined photothermal therapy for tumor. Nanotechnol. Biol. Med., 2016, 12(7), 2019-2029.
[99]
Zhao, T.; Liu, Y.; Gao, Z.; Gao, D.; Li, N.; Bian, Y.; Dai, K.; Liu, Z. Self-assembly and cytotoxicity study of PEG-modified ursolic acid liposomes. Mater. Boil. Appl., 2015, 53, 196-203.
[100]
Yang, G.; Yang, T.; Zhang, W.; Lu, M.; Ma, X.; Xiang, G. In vitro and In vivo antitumor effects of folate-targeted ursolic acid stealth liposome. J. Agric. Food Chem., 2014, 62(10), 2207-2215.
[101]
Wang, M.L.; Zhao, T.T.; Liu, Y.P.; Wang, Q.Q.; Xing, S.S.; Li, L.; Wang, L.G.; Liu, L.X.; Gao, D.W. Ursolic acid liposomes with chitosan modification: Promising antitumor drug delivery and efficacy. Mat. Sci. Eng. C-Mater., 2017, 71, 1231-1240.
[102]
Rao, W.; Wang, H.; Han, J.F.; Zhao, S.T.; Dumbleton, J.; Agarwal, P.; Zhang, W.J.; Zhao, G.; Yu, J.H.; Zynger, D.L.; Lu, X.B.; He, X.M. Chitosan-decorated doxorubicin-encapsulated nanoparticle targets and eliminates tumor reinitiating cancer stem-like cells. ACS Nano, 2015, 9(6), 5725-5740.
[103]
Jin, H.; Pi, J.; Yang, F.; Wu, C.; Cheng, X.; Bai, H.; Huang, D.; Jiang, J.; Cai, J.; Chen, Z.W. Ursolic acid-loaded chitosan nanoparticles induce potent anti-angiogenesis in tumor. Appl. Microbiol. Biotechnol., 2016, 100(15), 6643-6652.
[104]
Bally, F.; Garg, D.K.; Serra, C.A.; Hoarau, Y.; Anton, N.; Brochon, C.; Parida, D.; Vandamme, T.; Hadziioannou, G. Improved size-tunable preparation of polymeric nanoparticles by microfluidic nanoprecipitation. Polymer , 2012, 53(22), 5045-5051.
[105]
Zhang, H.; Li, X.; Ding, J.; Xu, H.; Dai, X.; Hou, Z.; Zhang, K.; Sun, K.; Sun, W. Delivery of ursolic acid (UA) in polymeric nanoparticles effectively promotes the apoptosis of gastric cancer cells through enhanced inhibition of cyclooxygenase 2 (COX-2). Int. J. Pharm., 2013, 441(1-2), 261-268.
[106]
Ge, Z-Q.; Du, X-Y.; Huang, X-N.; Qiao, B. Enhanced oral bioavailability of ursolic acid nanoparticles via antisolvent precipitation with TPGS1000 as a stabilizer. J. Drug Deliv. Sci. Technol., 2015, 29, 210-217.
[107]
Baishya, R.; Nayak, D.K.; Kumar, D.; Sinha, S.; Gupta, A.; Ganguly, S.; Debnath, M.C. Ursolic acid loaded plga nanoparticles: In vitro and in vivo evaluation to explore tumor targeting ability on B16F10 melanoma cell lines. Pharm. Res., 2016, 33(11), 2691-2703.
[108]
Chen, X.; Chen, J.; Li, B.; Yang, X.; Zeng, R.; Liu, Y.; Li, T.; Ho, R.J.; Shao, J. PLGA-PEG-PLGA triblock copolymeric micelles as oral drug delivery system: In vitro drug release and in vivo pharmacokinetics assessment. J. Colloid Interface Sci., 2017, 490, 542-552.
[109]
Antonio, E.; Antunes, O.D.J.; de Araujo, I.S.; Khalil, N.M.; Mainardes, R.M. Poly(lactic acid) nanoparticles loaded with ursolic acid: Characterization and in vitro evaluation of radical scavenging activity and cytotoxicity. Mat. Sci. Eng. C Mater., 2017, 71, 156-166.
[110]
Kaminskas, L.M.; McLeod, V.M.; Kelly, B.D.; Sberna, G.; Boyd, B.J.; Williamson, M.; Owen, D.J.; Porter, C.J.H. A comparison of changes to doxorubicin pharmacokinetics, antitumor activity, and toxicity mediated by PEGylated dendrimer and PEGylated liposome drug delivery systems. Nanomed-Nanotechnol., 2012, 8(1), 103-111.
[111]
Gao, Y.; Li, Z.; Xie, X.; Wang, C.; You, J.; Mo, F.; Jin, B.; Chen, J.; Shao, J.; Chen, H.; Jia, L. Dendrimeric anticancer prodrugs for targeted delivery of ursolic acid to folate receptor-expressing cancer cells: Synthesis and biological evaluation. Eur. J. Pharm. Sci., 2015, 70, 55-63.
[112]
Shen, Z.; Li, B.; Liu, Y.; Zheng, G.; Guo, Y.; Zhao, R.; Jiang, K.; Fan, L.; Shao, J. A Self-assembly nanodrug delivery system based on amphiphilic low generations of PAMAM dendrimers-ursolic acid conjugate modified by lactobionic acid for HCC targeting therapy. Nanomedicine , 14(2), 227-236.
[113]
Fan, W.; Shen, B.; Bu, W.; Chen, F.; He, Q.; Zhao, K.; Zhang, S.; Zhou, L.; Peng, W.; Xiao, Q.; Ni, D.; Liu, J.; Shi, J. A smart upconversion-based mesoporous silica nanotheranostic system for synergetic chemo-/radio-/photodynamic therapy and simultaneous MR/UCL imaging. Biomaterials, 2014, 35(32), 8992-9002.
[114]
Li, T.; Chen, X.; Liu, Y.; Fan, L.; Lin, L.; Xu, Y.; Chen, S.; Shao, J. pH-Sensitive mesoporous silica nanoparticles anticancer prodrugs for sustained release of ursolic acid and the enhanced anti-cancer efficacy for hepatocellular carcinoma cancer. Eur. J. Pharm. Sci., 2017, 96, 456-463.
[115]
Jiang, K.; Chi, T.; Li, T.; Zheng, G.; Fan, L.; Liu, Y.; Chen, X.; Chen, S.; Jia, L.; Shao, J. A smart pH-responsive nano-carrier as a drug delivery system for the targeted delivery of ursolic acid: suppresses cancer growth and metastasis by modulating P53/MMP-9/PTEN/CD44 mediated multiple signaling pathways. Nanoscale, 2017, 9(27), 9428-9439.
[116]
Zhao, R.; Li, T.; Zheng, G.; Jiang, K.; Fan, L.; Shao, J. Simultaneous inhibition of growth and metastasis of hepatocellular carcinoma by co-delivery of ursolic acid and sorafenib using lactobionic acid modified and pH-sensitive chitosan-conjugated mesoporous silica nanocomplex. Biomaterials, 2017, 143, 1-16.
[117]
Lopes, S.C.D.; Novais, M.V.M.; Teixeira, C.S.; Honorato-Sampaio, K.; Pereira, M.T.; Ferreira, L.A.M.; Braga, F.C.; Oliveira, M.C. Preparation, physicochemical characterization, and cell viability evaluation of long-circulating and pH-sensitive liposomes containing ursolic acid. BioMed Res. Int., 2013.
[118]
Zheng, G.R.; Shen, Y.L.; Zhao, R.R.; Chen, F.; Zhang, Y.; Xu, A.X.; Shao, J.W. Dual-targeting multifuntional mesoporous silica nanocarrier for codelivery of siRNA and ursolic acid to folate Receptor Overexpressing Cancer Cells. J. Agric. Food Chem., 2017, 65(32), 6904-6911.
[119]
Huang, P.; Wang, D.; Su, Y.; Huang, W.; Zhou, Y.; Cui, D.; Zhu, X.; Yan, D. Combination of small molecule prodrug and nanodrug delivery: amphiphilic drug–drug conjugate for cancer therapy. J. Am. Chem. Soc., 2014, 136(33), 11748-11756.
Call for Papers in Thematic Issues
31 July, 2024
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
13 May, 2024
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
30 September, 2024
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
05 August, 2024
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...read more
Related Journals
Anti-Cancer Agents in Medicinal Chemistry
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry
Current Bioactive Compounds
Combinatorial Chemistry & High Throughput Screening
Current Cancer Therapy Reviews
Current Diabetes Reviews
Current Drug Safety
Current Drug Targets
Current Drug Therapy
Current Drug Delivery
Related Books
Drug Addiction Mechanisms in the Brain
Software and Programming Tools in Pharmaceutical Research
Objective Pharmaceutics: A Comprehensive Compilation of Questions and Answers for Pharmaceutics Exam Prep
Medicinal Chemistry of Drugs Affecting Cardiovascular and Endocrine Systems
Frontiers in Clinical Drug Research - Anti-Cancer Agents
The Management of Metastatic Triple-Negative Breast Cancer: An Integrated and Expeditionary Approach
Advanced Pharmacy
Plant-derived Hepatoprotective Drugs
Cancer Genes
The Role of Chromenes in Drug Discovery and Development
Article Metrics
111
5
1
1