Abstract
Background: Scientists have extensively investigated curcumin, yielding many publications on treatments of cancer. Numerous derivatives of curcumin were synthesized, evaluated for their anti-oxidant and free-radical scavenging, SAR, ADME properties and tested in anticancer applications.
Objective: We decided to exploit curcumin as a bioactive core platform for carrying anticancer drugs, which likely possesses a carboxyl moiety for potential linkage to the carrier for drug delivery.
Methods: The goal of this work is to develop biolabile multifunctional curcumin platforms towards anticancer drug delivery, including determination of drug release profiling in hydrolytic media, in vitro cytotoxicity, antioxidant properties and blockage of relevant cell survival pathways.
Results: We report on a facile synthesis of the bioactive multifunctional curcumin-based platforms linked to a variety of anticancer drugs like amonafide and chlorambucil, and release of the drugs in a hydrolytic environment. The leading curcumin-based platform has presented antioxidant activity similar to curcumin, but with much more potent cytotoxicity in vitro in agreement with the augmented blockage of the NF-kB cell survival pathway.
Conclusion: The approach presented here may prove beneficial for bioactive curcumin-based delivery applications where multiple drug delivery is required in a consecutive and controlled mode.
Keywords: Curcumin, platform, anticancer, stability, bifunctional, antioxidant.
Graphical Abstract
[1]
Hatcher, H.; Planalp, R.; Cho, J.; Torti, F.M.; Torti, S.V. Curcumin: From ancient medicine to current clinical trials. Cell. Mol. Life Sci., 2008, 65, 1631-1652.
[2]
Corson, T.W.; Crews, C.M. Molecular understanding and modern application of traditional medicines: Triumphs and trials. Cell, 2007, 130, 769-774.
[3]
Bar-Sela, G.; Epelbaum, R.; Schaffer, M. Curcumin as an anti-cancer agent: Review of the gap between basic and clinical applications. Curr. Med. Chem., 2010, 17, 190-197.
[4]
Jurenka, J.S. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: A review of preclinical and clinical research. Altern. Med. Rev., 2009, 14, 141-153.
[5]
Hamaguchi, T.; Ono, K.; Yamada, M. Curcumin and Alzheimer’s disease. CNS Neurosci. Ther., 2010, 16, 285-297.
[6]
Ahmad, B.; Borana, M.S.; Chaudhary, A.P. Understanding curcumin-induced modulation of protein aggregation. Int. J. Biol. Macromol., 2017, 100, 89-96.
[7]
Oda, Y. Inhibitory effect of curcumin on SOS functions induced by UV irradiation. Mutat. Res. Lett., 1995, 348, 67-73.
[8]
Reddy, A.R.; Dinesh, P.; Prabhakar, A.S.; Umasankar, K.; Shireesha, B.; Raju, M.B. A comprehensive review on SAR of curcumin. Mini Rev. Med. Chem., 2013, 13, 1769-1777.
[9]
Cridge, B.J.; Larsen, L.; Rosengren, R.J. Curcumin and its derivatives in breast cancer: Current developments and potential for the treatment of drug-resistant cancers. Oncol. Discov., 2013, 1(1), 6.
[10]
Pillai, G.R.; Srivastava, A.S.; Hassanein, T.I.; Chauhan, D.P.; Carrier, E. Induction of apoptosis in human lung cancer cells by curcumin. Cancer Lett., 2004, 208, 163-170.
[11]
Wan, S.B.; Yang, H.; Zhou, Z.; Cui, Q.C.; Chen, D.; Kanwar, J.; Mohammad, I.; Dou, Q.P.; Chan, T.H. Evaluation of curcumin acetates and amino acid conjugates as proteasome inhibitors. Int. J. Mol. Med., 2010, 26, 447-455.
[12]
Bush, J.A.; Cheung, K-J.J.; Li, G. Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53. Exp. Cell Res., 2001, 271, 305-314.
[13]
Wilken, R.; Veena, M.S.; Wang, M.B.; Srivatsan, E.S. Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol. Cancer, 2011, 10, 12.
[14]
Anand, P.; Kunnumakkara, A.B.; Newman, R.A.; Aggarwal, B.B. Bioavailability of curcumin: Problems and promises. Mol. Pharm., 2007, 4, 807-818.
[15]
Zhang, Q.; Zhong, Y.; Yan, L.N.; Sun, X.; Gong, T.; Zhang, Z.R. Synthesis and preliminary evaluation of curcumin analogues as cytotoxic agents. Bioorg. Med. Chem. Lett., 2011, 21, 1010-1014.
[16]
Liang, G.; Shao, L.; Wang, Y.; Zhao, C.; Chu, Y.; Xiao, J.; Zhao, Y.; Li, X.; Yang, S. Exploration and synthesis of curcumin analogues with improved structural stability both in vitro and in vivo as cytotoxic agents. Bioorg. Med. Chem., 2009, 17, 2623-2631.
[17]
Vyas, A.; Dandawate, P.; Padhye, S.; Ahmad, A.; Sarkar, F. Perspectives on new synthetic curcumin analogs and their potential anticancer properties. Curr. Pharm. Des., 2013, 19, 2047-2069.
[18]
Lin, L.; Shi, Q.; Nyarko, A.K.; Bastow, K.F.; Wu, C.C.; Su, C.Y.; Shih, C.C.Y.; Lee, K.H. Antitumor agents. 250. Design and synthesis of new curcumin analogues as potential anti-prostate cancer agents. J. Med. Chem., 2006, 49, 3963-3972.
[19]
Yamakoshi, H.; Ohori, H.; Kudo, C.; Sato, A.; Kanoh, N.; Ishioka, C.; Shibata, H.; Iwabuchi, Y. Structure-activity relationship of C5-curcuminoids and synthesis of their molecular probes thereof. Bioorg. Med. Chem., 2010, 18, 1083-1092.
[20]
Ohori, H.; Yamakoshi, H.; Tomizawa, M.; Shibuya, M.; Kakudo, Y.; Takahashi, A.; Takahashi, S.; Kato, S.; Suzuki, T.; Ishioka, C.; Iwabuchi, Y.; Shibata, H. Synthesis and biolgical analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer. Mol. Cancer Ther., 2006, 5(10), 2563-2571.
[21]
Ferrari, E.; Pignedoli, F.; Imbriano, C.; Marverti, G.; Basile, V.; Venturi, E.; Saladini, M. Newly synthesized curcumin derivatives: crosstalk between chemico-physical properties and biological activity. J. Med. Chem., 2011, 54, 8066-8077.
[22]
Lin, L.; Shi, Q.; Su, C.Y.; Shih, C.C.Y.; Lee, K.H. Antitumor agents 247. New 4-ethoxycarbonyl ethylcurcumin analogs as potential antiandrogenic agents. Bioorg. Med. Chem., 2006, 14, 2527-2534.
[23]
Bayomi, S.M.; El-Kashef, H.A.; El-Ashmawy, M.B.; Nasr, M.N.A.; El-Sherbeny, M.A.; Badria, F.A.; Abou-Zeid, L.A.; Ghaly, M.A.; Abdel-Aziz, N.I. Synthesis and biological evaluation of new curcumin derivatives as antioxidant and antitumor agents. Med. Chem. Res., 2013, 22, 1147-1162.
[24]
Shao, W.Y.; Cao, Y.N.; Yu, Z.W.; Pan, W.J.; Qiu, X.; Bu, X.Z.; An, L.K.; Huang, Z.S.; Gu, L.Q.; Chan, A.S.C. Facile preparation of new unsymmetrical curcumin derivatives by solid-phase synthesis strategy. Tetrahedron Lett., 2006, 47, 4085-4089.
[25]
Shi, W.; Dolai, S.; Rizk, S.; Hussain, A.; Tariq, H.; Averick, S.; L’Amoreaux, W.; El-Idrissi, A.; Banerjee, P.; Raja, K. Synthesis of monofunctional curcumin derivatives, clicked curcumin dimer, and a PAMAM dendrimer curcumin conjugate for therapeutic applications. Org. Lett., 2007, 9, 5461-5464.
[26]
Tang, H.; Murphy, C.J.; Zhang, B.; Shen, Y.; Van Kirk, E.A.; Murdoch, W.J.; Radosz, M. Curcumin polymers as anticancer conjugates. Biomaterials, 2010, 31, 7139-7149.
[27]
Safavy, A.; Raisch, K.P.; Mantena, S.; Sanford, L.L.; Sham, S.W.; Krishna, N.R.; Bonner, J.A. Design and development of water-soluble curcumin conjugates as potential anticancer agents. J. Med. Chem., 2007, 50, 6284-6288.
[28]
Yen, F.L.; Wu, T.H.; Tzeng, C.W.; Lin, L.T.; Lin, C.C. Curcumin nanoparticles improve the physicochemical properties of curcumin and effectively enhance its antioxidant and antihepatoma activities. J. Agric. Food Chem., 2010, 58, 7376-7382.
[29]
Aggarwal, S.; Ndinguri, M.W.; Solipuram, R.; Wakamatsu, N.; Hammer, R.P.; Ingram, D.; Hansel, W. [DLys(6)]-luteinizing hormone releasing hormone-curcumin conjugate inhibits pancreatic cancer cell growth in vitro and in vivo. Int. J. Cancer, 2011, 129, 1611-1623.
[30]
Yallapu, M.M.; Jaggi, M.; Chauhan, S.C. Curcumin nanoformulations: A future nanomedicine for cancer. Drug Discov. Today, 2012, 17, 71-80.
[31]
Teiten, M.H.; Dicato, M.; Diederich, M. Hybrid curcumin compounds: A new strategy for cancer treatment. Molecules, 2014, 19, 20839-20863.
[32]
Liu, K.; Guo, T.L.; Chojnacki, J.; Lee, H.G.; Wang, X.; Siedlak, S.L.; Rao, W.; Zhu, X.; Zhang, S. Bivalent ligand containing curcumin and cholesterol as fluorescence probe for Aβ plaques in Alzheimer’s disease. ACS Chem. Neurosci., 2012, 3, 141-146.
[33]
Singh, R.K.; Rai, D.; Yadav, D.; Bhargava, A.; Balzarini, J.; De Clercq, E. Synthesis, antibacterial and antiviral properties of curcumin bioconjugates bearing dipeptide, fatty acids and folic acid. Eur. J. Med. Chem., 2010, 45, 1078-1086.
[34]
Freeman, C.L.; Swords, R.; Giles, F.J. Amonafide: A future in treatment of resistant and secondary acute myeloid leukemia? Expert Rev. Hematol., 2012, 5, 17-26.
[35]
Knauf, W.U.; Lissitchkov, T.; Aldaoud, A.; Liberati, A.M.; Loscertales, J.; Herbrecht, R.; Juliusson, G.; Postner, G.; Gercheva, L.; Goranov, S.; Becker, M.; Fricke, H.J.; Huguet, F.; Del Giudice, I.; Klein, P.; Merkle, K.; Montillo, M. Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: Updated results of a randomized phase III trial. Br. J. Haematol., 2012, 159, 67-77.
[36]
Wada, K.; Lee, J.Y.; Hung, H.Y.; Shi, Q.; Lin, L.; Zhao, Y.; Goto, M.; Yang, P.C.; Kuo, S.C.; Chen, H.W.; Lee, K.H. Novel curcumin analogs to overcome EGFR-TKI lung adenocarcinoma drug resistance and reduce EGFR-TKI-induced GI adverse effects. Bioorg. Med. Chem., 2015, 23, 1507-1514.
[37]
Bi, W.; Bi, Y.; Gao, X.; Yan, X.; Zhang, Y.; Harris, J.; Legalley, T.D.; Gibson, K.M.; Bi, L. Pharmacological protection of mitochondrial function mitigates acute limb ischemia/reperfusion injury. Bioorg. Med. Chem. Lett., 2016, 26, 4042-4051.
[38]
Sribalan, R.; Kirubavathi, M.; Banuppriya, G.; Padmini, V. Synthesis and biological evaluation of new symmetric curcumin derivatives. Bioorg. Med. Chem. Lett., 2015, 25, 4282-4286.
[39]
Arezki, A.; Brule, E.; Jaouen, G. Synthesis and structure-activity relationships of the first Ferrocenyl-Aryl-Hydantoin derivatives of the nonsteroidal Antiandrogen Nilutamide. Organometallics, 2009, 28, 1606-1609.
[40]
Changtam, C.; Hongmanee, P.; Suksamrarn, A. Isoxazole analogs of curcuminoids with highly potent multidrug-resistant antimycobacterial activity. Eur. J. Med. Chem., 2010, 45, 4446-4457.
[41]
Ragozin, E.; Redko, B.; Tuchinsky, E.; Rozovsky, A.; Albeck, A.; Grynszpan, F.; Gellerman, G. Biolabile peptidyl delivery systems toward sequential drug release. Biopolymers Pep. Sci., 2015, 106, 119-132.
[42]
Chen, C.; Wang, Z.; Zhang, Z.; Liu, X. Kang; Zhang, Y.; Ye, K. The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer’s disease. Proc. Natl. Acad. Sci. USA, 2018, 115(3), 578-583.
[43]
Zhang, X.; Lin, Y.; Gillies, R.J. Tumor pH and its measurement. J. Nucl. Med., 2010, 51(8), 1167-1170.
[44]
Bazylevich, A.; Patsenker, L.D.; Gellerman, G. Exploiting fluorescein based drug conjugates for fluorescentmonitoring in drug delivery. Dyes Pigments, 2017, 139, 460-472.
[45]
Gilad, Y.; Firer, M.A.; Rozovsky, A.; Ragozin, E.; Redko, B.; Albeck, A.; Gellerman, G. “Switch off/switch on” regulation of drug cytotoxicity by conjugation to a cell targeting peptide.. Eur. J. Med. Chem., 2014, 85, 139-146.
[46]
Fujisawa, S.; Atsumi, T.; Ishihara, M.; Kadoma, Y. Cytotoxicity, ROS-generation activity and radical-scavenging activity of curcumin and related compounds. Anticancer Res., 2004, 24, 563-569.
[47]
Sökmen, M.; Akram, K.M. The antioxidant activity of some curcuminoids and chalcones. Inflammopharmacology, 2016, 24, 81-86.
[48]
Bothon, F.T.D.; Debiton, E.; Avlessi, F.; Forestier, C.; Teulade, J-C.; Sohounhloue, D.K.C. in vitro biological effects of two anti-diabetic medicinal plants used in Benin as folk medicine. BMC Complement. Altern. Med., 2013, 13, 51.
[49]
Wang, W.; Abbruzzese, J.L.; Evans, D.B.; Larry, L.; Cleary, K.R.; Chiao, P.J. The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin. Cancer Res., 1999, 5, 119-127.
[50]
Bours, V.; Dejardin, E.; Goujon-Letawe, F.; Merville, M.P.; Castronovo, V. The NF-kappa B transcription factor and cancer: High expression of NF-kappa B- and I kappa B-related proteins in tumor cell lines. Biochem. Pharmacol., 1994, 47, 145-149.
[51]
Sovak, M.A.; Bellas, R.E.; Kim, D.W.; Zanieski, G.J.; Rogers, A.E.; Traish, A.M.; Sonenshein, G.E. Aberrant nuclear factor-κB/Rel expression and the pathogenesis of breast cancer. J. Clin. Invest., 1997, 100, 2952-2960.
[52]
Yang, J.; Richmond, A. Constitutive IκB kinase activity correlates with nuclear factor-κB activation in human melanoma cells. Cancer Res., 2001, 61, 4901-4909.
[53]
Devalaraja, M.N.; Wang, D.Z.; Ballard, D.W.; Richmond, A. Elevated constitutive IkappaB kinase activity and IkappaB-alpha phosphorylation in Hs294T melanoma cells lead to increased basal MGSA/GRO-alpha transcription. Cancer Res., 1999, 59, 1372-1377.
[54]
Liao, W.; Xiang, W.; Wang, F.F.; Wang, R.; Ding, Y. Curcumin inhibited growth of human melanoma A375 cells via inciting oxidative stress. Biomed. Pharmacother., 2017, 95, 1177-1186.
[55]
Liao, W.; Xiang, W.; Wang, F.F.; Wang, R.; Ding, Y. Curcumin inhibited growth of human melanoma A375 cells via inciting oxidative stress. Biomed. Pharmacother., 2017, 95, 1177-1186.
[56]
Zhao, G.; Han, X.; Zheng, S.; Li, Z.; Sha, Y.; Ni, J.; Sun, Z.; Qiao, S.; Song, Z. Curcumin induces autophagy, inhibits proliferation and invasion by downregulating AKT/mTOR signaling pathway in human melanoma cells. Oncol. Rep., 2016, 35, 1065-1074.
Related Books
Science of Spices and Culinary Herbs - Latest Laboratory, Pre-clinical, and Clinical Studies
Frontiers in Natural Product Chemistry
Therapeutic Use of Plant Secondary Metabolites
Therapeutic Implications of Natural Bioactive Compounds
Frontiers in Bioactive Compounds
Frontiers in Natural Product Chemistry
Frontiers in Natural Product Chemistry
Science of Spices and Culinary Herbs - Latest Laboratory, Pre-clinical, and Clinical Studies
Frontiers in Natural Product Chemistry
Frontiers in Natural Product Chemistry
Article Metrics
24
3