Maslinic Acid Inhibits Proliferation of Renal Cell Carcinoma Cell Lines and Suppresses Angiogenesis of Endothelial Cells

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Parth Thakor
Wenzhe Song
Ramalingam B. Subramanian
Vasudev R. Thakkar
David A. Vesey
Glenda C. Gobe


angiogenesis, maslinic acid, proliferating cell nuclear antigen, renal cell carcinoma, vascular endothelial growth factor


Despite the introduction of many novel therapeutics in clinical practice, metastatic renal cell carcinoma (RCC) remains a treatment-resistant cancer. As red and processed meat are considered risk factors for RCC, and a vegetable-rich diet is thought to reduce this risk, research into plant-based therapeutics may provide valuable complementary or alternative therapeutics for the management of RCC. Herein, we present the antiproliferative and antiangiogenic effects of maslinic acid, which occurs naturally in edible plants, particularly in olive fruits, and also in a variety of medicinal plants. Human RCC cell lines (ACHN, Caki-1, and SN12K1), endothelial cells (human umbilical vein endothelial cell line [HUVEC]), and primary cultures of kidney proximal tubular epithelial cells (PTEC) were treated with maslinic acid. Maslinic acid was relatively less toxic to PTEC when compared with RCC under similar experimental conditions. In RCC cell lines, maslinic acid induced a significant reduction in proliferation, proliferating cell nuclear antigen, and colony formation. In HUVEC, maslinic acid induced a significant reduction in capillary tube formation in vitro and vascular endothelial growth factor. This study provides a rationale for incorporating a maslinic acid–rich diet either to reduce the risk of developing kidney cancer or as an adjunct to existing antiangiogenic therapy to improve efficacy.

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1. Soerensen AV, Donskov F, Hermann GG, Jensen NV, Petersen A, Spliid H, et al. Improved overall survival after implementation of targeted therapy for patients with metastatic renal cell carcinoma: results from the Danish Renal Cancer Group (DARENCA) study-2. Eur J Cancer. 2014 Feb;50(3):553–62.
2. Koshkin VS, Rini BI. Emerging therapeutics in refractory renal cell carcinoma. Expert Opin Pharmacother. 2016 Jun;17(9):1225–32.
3. Jiménez-Valerio G, Martínez-Lozano M, Bassani N, Vidal A, Ochoa-de-Olza M, Suárez C, et al. Resistance to antiangiogenic therapies by metabolic symbiosis in renal cell carcinoma PDX models and patients. Cell Rep. 2016 May10;15(6):1134–43.
4. Lim SH, Hwang IG, Ji JH, Oh SY, Yi JH, Lim DH, et al. Intrinsic resistance to sunitinib in patients with metastatic renal cell carcinoma. Asia Pac J Clin Oncol. 2017 Feb;13(1):61–67.
5. Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009 Oct;10(10):992–1000.
6. Porta C, Sabbatini R, Procopio G, Paglino C, Galligioni E, Ortega C. Primary resistance to tyrosine kinase inhibitors in patients with advanced renal cell carcinoma: state-of-the-science. Expert Rev Anticancer Ther. 2012 Dec;12(12):1571–7.
7. Busch J, Seidel C, Weikert S, Wolff I, Kempkensteffen C, Weinkauf L, et al. Intrinsic resistance to tyrosine kinase inhibitors is associated with poor clinical outcome in metastatic renal cell carcinoma. BMC Cancer. 2011 Jul14;11:295.
8. Amin A, Gali-Muhtasib H, Ocker M, Schneider-Stock R. Overview of major classes of plant-derived anticancer drugs. Int J Biomed Sci. 2009 Mar;5(1):1–11.
9. Joshi M, Liu X, Belani CP. Taxanes, past, present, and future impact on non-small cell lung cancer. Anticancer Drugs. 2014 May;25(5):571–83.
10. Rohrmann S, Linseisen J, Overvad K, Lund Würtz AM, Roswall N, Tjonneland A, et al. Meat and fish consumption and the risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition. Int J Cancer. 2015 Mar1;136(5):E423-31.
11. Daniel CR, Schwartz KL, Colt JS, Dong LM. Meat-cooking mutagens and risk of renal cell carcinoma. Br J Cancer. 2011 Sep27;105(7):1096–104.
12. Hsu CC, Chow WH, Boffetta P, Moore L, Zaridze D, Moukeria A, et al. Dietary risk factors for kidney cancer in Eastern and Central Europe. Am J Epidemiol. 2007 Jul1;166(1):62–70.
13. Grieb SM, Theis RP, Burr D, Benardot D, Siddiqui T, Asal NR. Food groups and renal cell carcinoma: results from a case-control study. J Am Diet Assoc. 2009 Apr;109(4):656–67.
14. Rashidkhani B, Lindblad P, Wolk A. Fruits, vegetables and risk of renal cell carcinoma: a prospective study of Swedish women. Int J Cancer. 2005 Jan20;113(3):451–5.
15. Reyes-Zurita FJ, Rufino-Palomares EE, Lupianez JA, Cascante M. Maslinic acid, a natural triterpene from Olea europaea L., induces apoptosis in HT29 human colon-cancer cells via the mitochondrial apoptotic pathway. Cancer Lett. 2009 Jan8;273(1):44–54.
16. Lozano-Mena G, Sanchez-Gonzalez M, Juan ME, Planas JM. Maslinic acid, a natural phytoalexin-type triterpene from olives–a promising nutraceutical? Molecules. 2014 Aug4;19(8):11538–59.
17. Montilla MP, Agil A, Navarro MC, Jiménez MI, García-Granados A, Parra A, et al. Antioxidant activity of maslinic acid, a triterpene derivative obtained from Olea europaea. Planta Med. 2003 May;69(5):472–4.
18. Huang L, Guan T, Qian Y, Huang M, Tang X, Li Y, et al. Anti-­inflammatory effects of maslinic acid, a natural triterpene, in cultured cortical astrocytes via suppression of nuclear factor-kappa B. Eur J Pharmacol. 2011 Dec15;672(1–3):169–74.
19. Moneriz C, Mestres J, Bautista JM, Diez A, Puyet A. Multi-targeted activity of maslinic acid as an antimalarial natural compound. FEBS J. 2011 Aug;278(16):2951–61.
20. De Pablos LM, González G, Rodrigues R, García Granados A, Parra A, Osuna A. Action of a pentacyclic triterpenoid, maslinic acid, against Toxoplasma gondii. J Nat Prod. 2010 May28;73(5):831–4.
21. Liu J, Sun H, Duan W, Mu D, Zhang L. Maslinic acid reduces blood glucose in KK-Ay mice. Biol Pharm Bull. 2007 Nov;30(11):2075–8.
22. Parra A, Rivas F, Lopez PE, Garcia-Granados A, Martinez A, Albericio F, et al. Solution- and solid-phase synthesis and anti-HIV activity of maslinic acid derivatives containing amino acids and peptides. Bioorg Med Chem. 2009 Feb1;17(3):1139–45.
23. Park SY, Nho CW, Kwon DY, Kang YH, Lee KW, Park JH. Maslinic acid inhibits the metastatic capacity of DU145 human prostate cancer cells: possible mediation via hypoxia-inducible factor-1alpha signalling. Br J Nutr. 2013 Jan28;109(2):210–22.
24. Zhang S, Ding D, Zhang X, Shan L, Liu Z. Maslinic acid induced apoptosis in bladder cancer cells through activating p38 MAPK signaling pathway. Mol Cell Biochem. 2014 Jul;392(1–2):281–7.
25. Hsia TC, Liu WH, Qiu WW, Luo J, Yin MC. Maslinic acid induces mitochondrial apoptosis and suppresses HIF-1alpha expression in A549 lung cancer cells under normoxic and hypoxic conditions. Molecules. 2014 Nov28;19(12):19892–906.
26. Li C, Yang Z, Zhai C, Qiu W, Li D, Yi Z, Wang L, et al. Maslinic acid potentiates the anti-tumor activity of tumor necrosis factor alpha by inhibiting NF-kappaB signaling pathway. Mol Cancer. 2010 Apr6;9:73.
27. Morais C, Westhuyzen J, Pat B, Gobe G, Healy H. High ambient glucose is effect neutral on cell death and proliferation in human proximal tubular epithelial cells. Am J Physiol Renal Physiol. 2005 Aug;289(2):F401-9.
28. Morais C, Pat B, Gobe G, Johnson DW, Healy H. Pyrrolidine dithiocarbamate exerts anti-proliferative and pro-apoptotic effects in renal cell carcinoma cell lines. Nephrol Dial Transplant. 2006 Dec;21(12):3377–88.
29. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239–57.
30. Morais C, Gobe G, Johnson DW, Healy H. Anti-angiogenic actions of pyrrolidine dithiocarbamate, a nuclear factor kappa B inhibitor. Angiogenesis. 2009;12(4):365–79.
31. Morais C, Ebrahem Q, Anand-Apte B, Parat MO. Altered angiogenesis in caveolin-1 gene-deficient mice is restored by ablation of endothelial nitric oxide synthase. Am J Pathol. 2012 Apr;180(4):1702–14.
32. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar4;144(5):646–74.
33. Nam YJ, Mani K, Ashton AW, Peng CF, Krishnamurthy B, Hayakawa Y, et al. Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions. Mol Cell. 2004 Sep24;15(6):901–12.
34. Ola MS, Nawaz M, Ahsan H. Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem. 2011 May;351(1–2):41–58.
35. Bai X, Zhang Y, Jiang H, Yang P, Li H, Zhang Y, et al. Effects of maslinic acid on the proliferation and apoptosis of A549 lung cancer cells. Mol Med Rep. 2016 Jan;13(1):117–22.
36. Dirim A1, Haberal AN, Goren MR, Tekin MI, Peskircioglu L, Demirhan B, et al. VEGF, COX-2, and PCNA expression in renal cell carcinoma subtypes and their prognostic value. Int Urol Nephrol. 2008;40(4):861–8.
37. Amare Kadam PS, Varghese C, Bharde SH, Narasimhamoorthy NK, Desai S, Advani SH, et al. Proliferating cell nuclear antigen and epidermal growth factor receptor (EGFr) status in renal cell carcinoma patients with polysomy of chromosome 7. Cancer Genet Cytogenet. 2001 Mar;125(2):139–46.
38. Tang SW, Chang WH, Su YC, Chen YC, Lai YH, Wu PT, et al. MYC pathway is activated in clear cell renal cell carcinoma and essential for proliferation of clear cell renal cell carcinoma cells. Cancer Lett. 2009 Jan8;273(1):35–43.
39. Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol. 2005 Feb10;23(5):1028–43.
40. Posadas EM, Limvorasak S, Sharma S, Figlin RA. Targeting angiogenesis in renal cell carcinoma. Expert Opin Pharmacother. 2013 Nov;14(16):2221–36.
41. Takahashi A, Sasaki H, Kim SJ, Tobisu K, Kakizoe T, Tsukamoto T, et al. Markedly increased amounts of messenger RNAs for vascular endothelial growth factor and placenta growth factor in renal cell carcinoma associated with angiogenesis. Cancer Res. 1994 Aug1;54(15):4233–7.
42. Zhang X, Yamashita M, Uetsuki H, Kakehi Y. Angiogenesis in renal cell carcinoma: Evaluation of microvessel density, vascular endothelial growth factor and matrix metalloproteinases. Int J Urol. 2002 Sep;9(9):509–14.
43. Rioux-Leclercq N, Fergelot P, Zerrouki S, Leray E, Jouan F, Bellaud P, et al. Plasma level and tissue expression of vascular endothelial growth factor in renal cell carcinoma: a prospective study of 50 cases. Hum Pathol. 2007 Oct;38(10):1489–95.
44. Lin CC, Huang CY, Mong MC, Chan CY, Yin MC. Antiangiogenic Potential of Three Triterpenic Acids in Human Liver Cancer Cells. J Agric Food Chem. 2011 Jan26;59(2):755–62.
45. Ovesná Z, Vachálková A, Horváthová K, Tóthová D. Pentacyclic triterpenoic acids: new chemoprotective compounds. Minireview. Neoplasma. 2004;51(5):327–33.
46. Sohn KH, Lee HY, Chung HY, Young HS, Yi SY, Kim KW. Anti-angiogenic activity of triterpene acids. Cancer Lett. 1995 Aug1;94(2):213–8.
47. Sogno I, Vannini N, Lorusso G, Cammarota R, Noonan DM, Generoso L, et al. Anti-angiogenic activity of a novel class of chemopreventive compounds: oleanic acid terpenoids. Recent Results Cancer Res. 2009;181:209–12.
48. Staunton MJ, Gaffney EF. Tumor type is a determinant of susceptibility to apoptosis. Am J Clin Pathol. 1995 Mar;103(3):300–7.
49. Qazi AK, Hussain A, Aga MA, Ali S, Taneja SC, Sharma PR, et al. Cell specific apoptosis by RLX is mediated by NFκB in human colon carcinoma HCT-116 cells. BMC Cell Biol. 2014 Oct10;15:36.