EMAN RESEARCH PUBLISHING | Journal | <p>Anti-GBM potential of Rosmarinic acid and its synthetic derivatives via targeting IL17A mediated angiogenesis pathway</p>
Inflammation Cancer Angiogenesis Biology and Therapeutics | Impact 0.1 (CiteScore) | Online ISSN  2207-872X

Anti-GBM potential of Rosmarinic acid and its synthetic derivatives via targeting IL17A mediated angiogenesis pathway

Md Shamsuddin Sultan Khan A,C,E, Mohammad Adnan Iqbal B, Muhammad Asif A, Tabinda Azam B, Majed Al-Mansoub A, Rosenani S. M. A. Haque B, Mohammed Khadeer Ahamed Basheer C, Aman Shah Abdul Majid D, Amin Malik Shah Abdul Majid A,C,E*

+ Author Affiliations

Journal of Angiotherapy 3(1) 097-122 https://doi.org/10.25163/angiotherapy.21206512012110519

Submitted: 20 December 2018  Revised: 12 April 2019  Published: 11 May 2019 

Metal salts and base rosmarinates demonstrated potent anti-GBM efficacy as IL17A inhibitor with minimal toxicity.   


Glioblastoma (GBM) is a highly angiogenic malignant primary brain tumor with very poor patient survival rates. Here, we present Rosmarinic acid and its new salt and base derivatives that show potential anti-glioblastoma (anti-GBM) activity via disruption of IL17A-mediated downstream angiogenesis pathway. These new compounds were rationally designed, synthesized and the oral CNS physicochemical properties were determined. The anti-GBM activity of the compounds were determined using cell migration and proliferation assays in U87 MG, DBTRG MG and EA.hy926 cells. The compounds activity on IL17A and VEGF expression was determined using ELISA and apoptotic activity was measured by caspase assays. The compounds showed stability in serum and at different pH similar to Rosmarinic acid stoichiometry.  Moreover, the salt derivatives were highly hydrophilic and bases were highly lipophilic. These derivatives showed blood-brain barrier permeability >2 fold more than rosmarinic acid (P<0.001). ROS were differentially expressed after treatment with salt and base rosmarinates in U87 MG (P<0.0001). The compounds showed cytostatic and anti-angiogenic activity. The IC50 of the silver salts was found to be > 1200 µg/ml thus excluding them from being classed as toxic compounds. In conclusion, metal salts and base rosmarinates demonstrated potent anti-GBM efficacy as IL17A inhibitor with minimal toxicity.   

Key Words: IL17A, Chemotherapy, Glioblastoma, Anti-angiogenic activity, Rosmarinic acid, Caffeic acid, Synthetic derivatives



ACD/ilab2, version 12.01. (2015). Advanced Chemistry Development, Inc., (Toronto, ON, Canada), www.acdlabs.com.
Angelo LS, Kurzrock R. (2007). Vascular endothelial growth factor and its relationship to inflammatory mediators. Clin Cancer Res., 13(10), 2825-30.
Aldred, S.; Bennet, S.; Mecocci, P. (2010). Increased low-density lipoprotein oxidation, but not total plasma protein oxidation, in Alzheimer's disease. Clincal Biochemistry, 43, 267-271.
Bennet, S.; Grant, M. M.; Aldred, S. (2009). Oxidative Stress in Vascular Dementia and
Alzheimers Disease: A Common Pathology. Journal of Alzheimer's Disease, 17, 245-257.
Benzie IFF and Strain JJ. (1996). The ferric reducing ability of plasma (FRAP) as a measure of 'antioxidant power': the FRAP assay. Anal Biochem., 239, 70-76.
Cancer Incidence in Peninsular Malaysia, Malaysian Natinal Cancer Council (MAKNA). (2006).
Dohle DS, Pasa SD, Gustmann S, Laub M, Wissler JH, Jennissen HP, Dünker N. (2009). Chick ex ovo culture and ex ovo CAM assay: how it really works. Journal of Visual Experiment, 30(33), Pii, 1620.
PMid:19949373 PMCid:PMC3157849
Douglas E. V. Pires, Tom L. Blundell, David B. (2015). Ascher, predicting small-molecule pharmacokinetic properties using graph-based signatures. J. Med. Chem., 58 (9), 4066-4072.
PMid:25860834 PMCid:PMC4434528
Falé PL, Madeira PJ, Florêncio MH, Ascensão L, Serralheiro ML. (2011). Function of Plectranthus barbatus herbal tea as neuronal acetylcholinesterase inhibitor. Food Funct., 2(2), 130-6.
Georgina N. Masoud, Wei Li. (2015). HIF-1α pathway: role,regulationandintervention for cancer therapy, Acta Pharmaceutica Sinica B, 5(5):378-389
PMid:26579469 PMCid:PMC4629436
Geran, R.I., Greenberg, N.H., Macdonald, M.M., Schumacher, A.M. and Abbott, B.J.
(1971). Protocols for screening chemical agents and natural products against animal tumours and
other biological systems. Canada Chemotherapy Report, 12, 59-61.
Hayashi, T.; Shisido, N.; Nakayama, K.; Nunomura, A.; Smith, M. A.; Perry, G.; Nakamura, M. (2007). Lipid peroxidation and 4-hydroxy-2-nonenal formation by copper ion bound to
amyloid-β peptide. Free Radical Biology and Medicine, 43, 1552-1559.
Hu J, Ye H, Zhang D, Liu W, Li M, Mao Y, Lu Y. (2013). U87 MG glioma cells overexpressing IL-17 acclerate early-stage growth in vivo and cause a higher level of CD31 mRNA expression in tumor tissues. Oncol Lett., 6(4), 993-999.
PMid:24137452 PMCid:PMC3796409
Jafari, S. F., Ahamed, K., Mohamed, B., Iqbal, M. A., Al Suede, F. S. R., Khalid, S. H., Haque, R. A., Nassar, Z. D., Umar, M. I. &Majid, A. (2014). Increased aqueous solubility and proapoptotic activity of potassium koetjapate against human colorectal cancer cells. Journal of Pharmacy and Pharmacology., 66(10), 1394-1409.
Khan Md Shamsuddin Sultan, Syeed Sharif Hossain, Uddin Md Hanif, Akter Lucky, Ullah Md Asmat et al. (2013). Screening and evaluation of antioxidant, antimicrobial, cytotoxic, thrombolytic and membrane stabilizing properties of the methanolic extract and solvent-solvent partitioning effect of Vitex negundo Bark. Asian Pac J Trop Dis., 3(5), 393-400.
Khan Md Shamsuddin Sultan, Salam Md Abdus, Haque Rosenani S.M.A., Abdul Majid Amin Malik Shah, Abdul Majid Aman Shah Bin, Asif Muhammad, Basheer Mohamed Khadeer Ahamed, Tabana Yaseer M. (2016a). Synthesis, cytotoxicity, and long-term single dose anti-cancer pharmacological evaluation of dimethyltin(IV) complex of N(4)-methylthiosemicarbazone (having ONS donor ligand). Cogent Biology, 2, 1154282.
Khan MS, Majid AM, Iqbal MA, Majid AS, Al-Mansoub M, Haque RS. (2016b). Designing the angiogenic inhibitor for brain tumor via disruption of VEGF and IL17A expression. Eur J Pharm Sci., 93, 304-18.
Kay F. Macleod. (2008). The role of the RB tumour suppressor pathway in oxidative stress responses in the haematopoietic system. Nat Rev Cancer. 8(10). 769-781.
PMid:18800074 PMCid:PMC2989879
Kuzuya, M.; Yamada, K.; Hayashi, T.; Funaki, C.; Naito, M.; Asai, K.; Kuzuya, F. (1992). Role of lipoprotein-copper complex in copper-catalysed peroxidation of low-density lipoprotein. Biochimica et Biophysica Acta, 1123, 334-341.
Lamaison, J. L., Petitjean-Freytet, C. and Carnat, A. (1991). Medicinal Lamiaceae with antioxidant properties, a potential source of rosmarinic acid. Pharm. Acta. Helv., 66(7), 185-188
LeadIT 2.1.9. (2015). BioSolveIT GmbH, St. Augustin, Germany.
Mohan, S., Abdelwahab, S.I., Kamalidehghan, B., Syam, S., May, K.S., Harmal, N.S.M., Shafifiyaz, N., Hadi, A.H.A., Hashim, N.M., Rahmani, M., Taha, M.M.E., Cheah, S.C., Zajmi, A. (2012). Involvement of NF-kB and Bcl2/Bax signaling pathways in the apoptosis of MCF7 cells induced by a xanthone compound Pyranocycloartobiloxanthone A. Phytomedicine, 19, 1007-1015.
Matsuzawa A. and Ichijo H., (2008). Redox control of cell fate by MAP kinase: physiological roles of ASK1-MAP kinase pathway in stress signaling. Biochimica et Biophysica Acta, 1780(11), 1325-1336.
Nevins JR. (2001). The Rb/E2F pathway and cancer. Hum Mol Genet., 10(7), 699-703.
Neckers, L., and Ivy, P. S., 2003. Curr. Opin. Oncol. 15. 419-424.
Nicosia R, Ottinetti A. (1990). Growth of microvessels in serum-free matrix culture of rat aorta: a quantitative assay of angiogenesis in vitro. Lab Invest., 63, 115-122.
Okoh V O, Garba N A , Penney R B , Das J, Deoraj A, Singh K P , Sarkar S, Felty Q, Yoo C, Jackson R M and Roy D. (2015). Redox signalling to nuclear regulatory proteins by reactive oxygen species contributes to oestrogen-induced growth of breast cancer cells. British Journal of Cancer, 112, 1687-1702.
PMid:25965299 PMCid:PMC4430710
Oztekin Algul, Alper Karabulut, Necmiye Canacankatan, Aysegul Gorur, Nehir Sucu and Ozden Vezir. (2012). Apoptotic and Anti-Angiogenic Effects of Benzimidazole Compounds: Relationship with Oxidative Stress Mediated Ischemia/Reperfusion Injury in Rat Hind Limb. Antiinflamm Antiallergy Agents Med Chem., 11(3), 267-75.
Patel, R. P.; Svistunenko, D.; Wilson, M. T.; Darley-Usmar, V. M. (1997). Reduction of Cu(II) by lipid hydroperoxides: implications for the copper-dependent oxidation of low density
PMid:9065759 PMCid:PMC1218208
lipoprotein. Biochemical Journal, 322, 425-433.
Pathi SS, Jutooru I, Chadalapaka G, Sreevalsan S, Anand S, Thatcher GR, and Safe S., (2011). GT-094, a NO-NSAID, inhibits colon cancer cell growth by activation of a reactive oxygen species-microRNA-27a: ZBTB10-specificity protein pathway. Mol Cancer Res. 9, 195-202.
PMid:21156786 PMCid:PMC3069691
Paladugu M, Thakur A, Lum LG, Mittal S, Parajuli P. (2013). Generation and immunologic functions of Th17 cells in malignant gliomas. Cancer Immunol Immunother, 62, 75-86.
PMid:22752645 PMCid:PMC3888106
Pratt, W. B., and Toft, D. O., (2003). Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp. Biol. Med. 228, 111-133.
Polla BS, Kantengwa S, Francois D. Salvioli S, Franceschi C, Marsac C et al., (1996). Mitochondria are selective targets for the protective effects of heat shock against oxidative injury. Proc Natl Acad Sci, 93, 6458-6463.
PMid:8692837 PMCid:PMC39045
Petersen M., Abdullah Y., Benner J., Eberle D., Gehlen K., Hücherig S., Janiak V., Kim K. H., Sander M., Weitzel C., Wolters S. (2009). Evolution of rosmarinic acid biosynthesis.
Phytochemistry, 70 (15-16), 1663-1679.
Petersen M., Simmonds. M. S. (2003). Rosmarinic acid. Phytochemistry, 62(2), 121-125.
Pinchuk, I.; Lichtenberg, D. (2002). The mechanism of action of antioxidants against lipoprotein peroxidation, evaluation based on kinetic experiments. Progress in Lipid Research, 41, 279- 314.
Scheckel KA, Degner SC, Romagnolo DF. (2008). Rosmarinic acid antagonizes activator protein-1-dependent activation of cyclooxygenase-2 expression in human cancer and nonmalignant cell lines. J Nutr., 138(11), 2098-105.
PMid:18936204 PMCid:PMC3151436
Sharmila R, Manoharan S. (2012). Anti-tumor activity of rosmarinic acid in 7,12-dimethylbenz(a)anthracene (DMBA) induced skin carcinogenesis in Swiss albino mice. Indian J Exp Biol., 50(3), 187-94.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC et al. (2009). Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol., 10(5), 459-66.
Syed, H. K., Iqbal, M. A., Haque, R. A. &Peh, K.-K. (2015). Synthesis, characterization and antibacterial activity of a curcumin-silver (I) complex. Journal of Coordination Chemistry., 68(6), 1088-1100.
Talley NJ, Zinsmeister AR, Weaver A, DiMagno EP, Carpenter HA, Perez-Perez GI, Blaser MJ. (1991). Gastric adenocarcinoma and Helicobacter pylori infection. J Natl Cancer Inst., 83(23), 1734-9.
Taub ME, Podila L, Ely D, Almeida I., (2005). Functional assessment of multiple P-glycoprotein (P-gp) probe substrates: influence of cell line and modulator concentration on P-gp activity. Drug Metab Dispos. 33 (11), 1679-87.
Torres M. and Forman H. J., (2003). Redox signaling and the MAP kinase pathways. BioFactors, 17(1-4), 287-296.
Tuettenberg J, Friedel C, Vajkoczy P., (2006). Angiogenesis in malignant glioma-a target for antitumor therapy. Crit Rev Oncol Hematol. 59, 181-193
Vikram Devgan, Abigail Harris, Qiong Jiang, and Scott Pattison. (2012). Cignal Reporter Assay Kit: A high-performance tool for assessing the functions of genes, biologics, and small molecule compounds, QIAGEN, 6951 Executive Way, Frederick, Maryland 21703, USA.
Volkamer A, Kuhn D, Rippmann F, Rarey M. (2012). DoGSiteScorer: a web server for automatic binding site prediction, analysis and druggability assessment. Bioinformatics., 28(15), 2074-5.
Wainwright DA, Sengupta S, Han Y, Ulasov IV, Lesniak MS. (2010). The presence of IL-17A and T helper 17 cells in experimental mouse brain tumors and human glioma. PLoS One 2010, 5, e15390.
PMid:21060663 PMCid:PMC2963644
Wang, C., L. Wu, K. Bulek, B. N. Martin, J. A. Zepp, Z. Kang, C. Liu, et al., (2012). Psoriasis-associated variant Act1 D10N with impaired regulation by Hsp90. Nature immunology. 14 (1), 72-81.
PMid:23202271 PMCid:PMC3522792
Wang Q, Rager JD, Weinstein K, Kardos PS, Dobson GL, Li J, et al. (2005). Evaluation of the MDR-MDCK cell line as a permeability screen for the blood-brain barrier. Int J Pharm., 288(2), 349-59.
Zhang, Q. Ma Y, Cheng YF, Li WJ, Zhang Z, Chen SY., (2011). Involvement of reactive oxygen species in 2 methoxyestradiol-induced apoptosis in human neuroblastoma cells. Cancer Lett., 31, 201-210.
PMid:21978530 PMCid:PMC3224534
Zhou P, Sha H, Zhu J. (2010). The role of T-helper 17 (Th17) cells in patients with medulloblastoma. J Int Med Res, 38, 611-619.

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