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Curcumin based combination therapy for anti-breast cancer: from in vitro drug screening to in vivo efficacy evaluation

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Abstract

While drug resistance appears to be an inevitable problem of an increasing number of anticancer drugs in monotherapy, combination drug therapy has become a prosperous method to reduce the administered total drug dosages as well as overcome the drug resistance of carcinoma cells. Curcumin, considered to possess multifaceted roles in cancer treatment according to its multiple anti-neoplastic mechanisms as a depressor of chemoresistance, can significantly facilitate its anti-cancer functions and improve therapeutic effects via combination usage with a variety of other drugs with different reaction mechanisms. To explore this possibility, four anti-cancer chemotherapeutic agents that all possess a certain degree of drug resistance problems, including three tyrosine kinase inhibitors (erlotinib, sunitinib and sorafenib) that are acting on different cell pathways and a typical anticancer drug doxorubicin, were combined with curcumin individually to examine the synergistic anti-tumor effect both in vitro and in vivo. Results revealed that sunitinib combined with curcumin at the molar ratio of 0.46 yielded the most potent synergistic effect in vitro, and was therefore chosen for further animal evaluation. To further enhance the anticancer effect, bovine serum albumin (BSA) nanoparticles were utilized as a carrier to deliver the selected drug combination in situ. Preliminary in vivo findings confirmed our hypothesis of being able to maintain a similar injected drug ratio for prolonged time periods in tested animals by our approach, thereby maximizing the therapeutic potency yet minimizing the toxicity of these drugs. This work could open up a new avenue on combination drug therapy and realization the clinical utility of such drugs.

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References

  1. Basnet P, Skalko-Basnet N. Curcumin: An anti-inflammatory molecule from a curry spice on the path to cancer treatment. Molecules (Basel. Switzerland), 2011, 16(12): 4567–4598

    CAS  Google Scholar 

  2. Boyanapalli S S, Kong A N. Curcumin, the king of spices: Epigenetic regulatory mechanisms in the prevention of cancer, neurological and inflammatory diseases. Current Pharmacolog. Reports, 2015, 1(2): 129–139

    CAS  Google Scholar 

  3. Teiten M H, Dicato M, Diederich M. Curcumin as a regulator of epigenetic events. Molecular Nutrition & Foo. Research, 2013, 57 (9): 1619–1629

    CAS  Google Scholar 

  4. Shehzad A, Lee Y S. Molecular mechanisms of curcumin action: Signal transduction. BioFactors (Oxford. England), 2013, 39(1): 27–36

    CAS  Google Scholar 

  5. Bose S, Panda A K, Mukherjee S, Sa G. Curcumin and tumor immune-editing: Resurrecting the immune system. Cel. Division, 2015, 10(1): 6

    Article  Google Scholar 

  6. Li Y, Zhang T. Targeting cancer stem cells by curcumin and clinical applications. Cance. Letters, 2014, 346(2): 197–205

    CAS  Google Scholar 

  7. Bordoloi D, Roy N K, Monisha J, Padmavathi G, Kunnumakkara A B. Multi-targeted agents in cancer cell chemosensitization: What we learnt from curcumin thus far. Recent Patents on Anti-cancer Dru. Discovery, 2016, 11(1): 67–97

    CAS  Google Scholar 

  8. Saha S, Adhikary A, Bhattacharyya P, Das T, Sa G. Death by design: Where curcumin sensitizes drug-resistant tumors. Anticance. Research, 2012, 32(7): 2567–2584

    CAS  Google Scholar 

  9. Chang R, Sun L, Webster T J. Selective inhibition of MG-63 osteosarcoma cell proliferation induced by curcumin-loaded selfassembled arginine-rich-RGD nanospheres. International Journal o. Nanomedicine, 2015, 10: 3351–3365

    CAS  Google Scholar 

  10. Collins H M, Abdelghany M K, Messmer M, Yue B, Deeves S E, Kindle K B, Mantelingu K, Aslam A, Winkler G S, Kundu T K, Heery D M. Differential effects of garcinol and curcumin on histone and p53 modifications in tumor cells. BM. Cancer, 2013, 13(1): 37

    CAS  Google Scholar 

  11. Bozic I, Reiter J G, Allen B, Antal T, Chatterjee K, Shah P, Moon Y S, Yaqubie A, Kelly N, Le D T, Lipson E J, Chapman P B, Diaz L A Jr, Vogelstein B, Nowak M A. Evolutionary dynamics of cancer in response to targeted combination therapy. eLife, 2013, 2: e00747

    Article  Google Scholar 

  12. Brahmbhatt M, Gundala S R, Asif G, Shamsi S A, Aneja R. Ginger phytochemicals exhibit synergy to inhibit prostate cancer cell proliferation. Nutrition an. Cancer, 2013, 65(2): 263–272

    CAS  Google Scholar 

  13. Gotink K J, Verheul H M. Anti-angiogenic tyrosine kinase inhibitors: What is their mechanism of action. Angiogenesis, 2010, 13(1): 1–14

    Article  CAS  Google Scholar 

  14. Shen G, Liu T, Wang Q, Jiang M, Shi J. Spectroscopic and molecular docking studies of binding interaction of gefitinib, lapatinib and sunitinib with bovine serum albumin (BSA). Journal of Photochemistry and Photobiology B. Biology, 2015, 153: 380–390

    Article  CAS  Google Scholar 

  15. Cao H, Wang Y, He X, Zhang Z, Yin Q, Chen Y, Yu H, Huang Y, Chen L, Xu M, Gu W, Li Y. Codelivery of sorafenib and curcumin by directed self-assembled nanoparticles enhances therapeutic effect on hepatocellular carcinoma. Molecula. Pharmaceutics, 2015, 12 (3): 922–931

    Article  CAS  Google Scholar 

  16. Llovet J M, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J F, de Oliveira A C, Santoro A, Raoul J L, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten T F, Galle P R, Seitz J F, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J. Sorafenib in advanced hepatocellular carcinoma. New England Journal o. Medicine, 2008, 359(4): 378–390

    CAS  Google Scholar 

  17. Desandes E. Survival from adolescent cancer. Cancer Treatmen. Reviews, 2007, 33(7): 609–615

    Google Scholar 

  18. Li S, Sun W, Wang H, Zuo D, Hua Y, Cai Z. Research progress on the multidrug resistance mechanism of osteosarcoma chemotherapy and reversal. Tumou. Biology, 2015, 36(3): 1329–1338

    CAS  Google Scholar 

  19. Nedelcu T, Kubista B, Koller A, Sulzbacher I, Mosberger I, Arrich F, Trieb K, Kotz R, Toma C D. Livin and Bcl-2 expression in highgrade osteosarcoma. Journal of Cancer Research and Clinica. Oncology, 2007, 134(2): 237–244

    Google Scholar 

  20. Rajkumar T, Yamuna M. Multiple pathways are involved in drug resistance to doxorubicin in an osteosarcoma cell line. Anti-Cance. Drugs, 2008, 19(3): 257–265

    CAS  Google Scholar 

  21. Guo L, Shen Y, Zhao X, Guo L, Yu Z, Wang D, Liu L, Liu J. Curcumin combined with oxaliplatin effectively suppress colorectal carcinoma in vivo through inducing apoptosis. Phytotherap. Research, 2015, 29(3): 357–365

    CAS  Google Scholar 

  22. Jonker M J, Svendsen C, Bedaux J J, Bongers M, Kammenga J E. Significance testing of synergistic/antagonistic, dose level-dependent, or dose ratio-dependent effects in mixture dose-response analysis. Environmental Toxicology an. Chemistry, 2005, 24(10): 2701–2713

    CAS  Google Scholar 

  23. Hu C, Aryal S, Zhang L. Nanoparticle-assisted combination therapies for effective cancer treatment. Therapeuti. Delivery, 2010, 1(2): 323–334

    Article  CAS  Google Scholar 

  24. Ashton J C. Drug combination studies and their synergy quantification using the Chou-Talalay Method-Letter. Cance. Research, 2015, 75(11): 2400

    CAS  Google Scholar 

  25. Tardi P, Johnstone S, Harasym N, Xie S, Harasym T, Zisman N, Harvie P, Bermudes D, Mayer L. In vivo maintenance of synergistic cytarabine: Daunorubicin ratios greatly enhances therapeutic efficacy. Leukemi. Research, 2009, 33(1): 129–139

    CAS  Google Scholar 

  26. Mayer L D, Harasym T O, Tardi P G, Harasym N L, Shew C R, Johnstone S A, Ramsay E C, Bally M B, Janoff A S. Ratiometric dosing of anticancer drug combinations: Controlling drug ratios after systemic administration regulates therapeutic activity in tumorbearing mice. Molecular Cance. Therapeutics, 2006, 5(7): 1854–1863

    CAS  Google Scholar 

  27. Farokhzad O C, Langer R. Impact of nanotechnology on drug delivery. AC. Nano, 2009, 3(1): 16–20

    CAS  Google Scholar 

  28. He H, David A, Chertok B, Cole A, Lee K, Zhang J, Wang J, HuangY, Yang V C. Magnetic nanoparticles for tumor imaging and therapy: A so-called theranostic system. Pharmaceutica. Research, 2013, 30(10): 2445–2458

    CAS  Google Scholar 

  29. He H, Ye J, Sheng J, Wang J, Huang Y, Chen G, Wang J, Yang V C. Overcoming oral insulin delivery barriers: Application of cell penetrating peptide and silica-based nanoporous composites. Frontiers of Chemical Science an. Engineering, 2013, 7(1): 9–19

    Google Scholar 

  30. He H, Liang Q, ShinMC, Lee K, Gong J, Ye J, Liu Q, Wang J, Yang V C. Significance and strategies in developing delivery systems for bio-macromolecular drugs. Frontiers of Chemical Science an. Engineering, 2013, 7(4): 496–507

    CAS  Google Scholar 

  31. Parhi P, Mohanty C, Sahoo S K. Nanotechnology-based combinational drug delivery: An emerging approach for cancer therapy. Drug Discover. Today, 2012, 17(17-18): 1044–1052

    CAS  Google Scholar 

  32. Yamasaki K, Chuang V T, Maruyama T, Otagiri M. Albumin-drug interaction and its clinical implication. Biochimica et Biophysic. Acta, 2013, 1830(12): 5435–5443

    CAS  Google Scholar 

  33. Lee H J, Bergen P J, Bulitta J B, Tsuji B, Forrest A, Nation R L, Li J. Synergistic activity of colistin and rifampin combination against multidrug-resistant Acinetobacter baumannii in an in vitro pharmacokinetic/pharmacodynamic model. Antimicrobial Agents an. Chemotherapy, 2013, 57(8): 3738–3745

    CAS  Google Scholar 

  34. Allen T M, Cullis P R. Drug delivery systems: Entering the mainstream. Science, 2004, 303(5665): 1818–1822

    Article  CAS  Google Scholar 

  35. Torchilin V P. Targeted pharmaceutical nanocarriers for cancer therapy and imaging. AAP. Journal, 2007, 9(2): E128–E147

    CAS  Google Scholar 

  36. Kratz F. Albumin as a drug carrier: Design of prodrugs, drug conjugates and nanoparticles. Journal of Controlle. Release, 2008, 132(3): 171–183

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China

    Sunhui Chen, Qiuling Liang, Shuping Xie, Zhili Yu, Lu Sun, Huining He & Victor C. Yang

  2. Collaborative Innovation Center of Chemical Science and Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China

    Ergang Liu

  3. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinjudaero, Jinju, Gyeongnam, 660-751, Republic of Korea

    Meong Cheol Shin

  4. Department of Pharmacy, Ewha Womans University, 11-1 Daehyun-dong, Seodaemun-gu, Seoul, 120-750, Republic of Korea

    Seung Jin Lee

  5. Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109-1065, USA

    Victor C. Yang

  6. Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea

    Victor C. Yang

Authors
  1. Sunhui Chen
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  2. Qiuling Liang
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  3. Shuping Xie
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  4. Ergang Liu
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  5. Zhili Yu
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  6. Lu Sun
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  7. Meong Cheol Shin
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  8. Seung Jin Lee
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  9. Huining He
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  10. Victor C. Yang
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Corresponding authors

Correspondence to Huining He or Victor C. Yang.

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These authors contributed equally to this work.

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Chen, S., Liang, Q., Xie, S. et al. Curcumin based combination therapy for anti-breast cancer: from in vitro drug screening to in vivo efficacy evaluation. Front. Chem. Sci. Eng. 10, 383–388 (2016). https://doi.org/10.1007/s11705-016-1574-2

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  • DOI: https://doi.org/10.1007/s11705-016-1574-2

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