Interactive anticancer effect of nanomicellar curcumin and galbanic acid combination therapy with some common chemotherapeutics in colon carcinoma cells

Document Type : Original Research Article


1 School of Medicine, Birjand University of Medical Sciences, Birjand, Iran

2 Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran.

3 Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

4 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

5 Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran

6 Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.

7 Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.


Objective: In the current investigation, we aimed to study the combined cytotoxicity of curcumin, as a nanomicellar formulation, and galbanic acid (Gal), dissolved in DMSO against the murine C26 and human Caco-2 colon carcinoma cells. Further, curcumin potential for cisplatin and doxorubicin (Dox) co-therapy was studied.
Materials and Methods: The combined cytotoxic effect of these phytochemicals at varying dose ratios were examined using the MTT colorimetric assay. Moreover, the time-dependent toxicity of curcumin, cisplatin, Dox, and pegylated liposomal Dox (Doxil) was determined. The interactive anti-proliferative behavior of these compounds was examined using the CompuSyn software.
Results: Nanomicellar curcumin showed considerable cytotoxicity in C26 cells 24 hr post-treatment. Co-treatment of cells with curcumin nanomicelles: Gal had a synergistic effect in C26 (at 10:1 molar ratio), and Caco-2 (at 1:5 molar ratio) cell lines in cell cultures. Nanomicellar curcumin showed strong and mild synergistic inhibitory effects in C26 cells when co-administered with Doxil and cisplatin, respectively.
Conclusion: Curcumin nanomicelles and Gal had a synergistic effect in C26 and Caco-2 cell lines. It is speculated that nanomicellar curcumin shows synergistic cancer cell killing if administered 24-hr post-injection of Doxil and cisplatin.


Main Subjects

Ahmadi F, Shokoohinia Y, Javaheri S, Azizian H. 2017. Proposed binding mechanism of galbanic acid extracted from Ferula assa-foetida to DNA.J Photochem Photobiol B, 166: 63-73.
Ahmadi M, Agah E, Nafissi S, Jaafari MR, Harirchian MH, Sarraf P, Faghihi-Kashani S, Hosseini SJ, Ghoreishi A, Aghamollaii V, Hosseini M, Tafakhori A. 2018. Safety and efficacy of nanocurcumin as add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a pilot randomized clinical trial. Neurotherapeutics, 152: 430-438.
Barenholz Y. 2012. Doxil®-the first FDA-approved nano-drug: lessons learned. J Control Release, 1602: 117-134.
Chou T. 2006.Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev, 58: 621-681.
Greco F, Vicent MJ. 2009. Combination therapy: opportunities and challenges for polymer-drug conjugates as anticancer nanomedicines. Adv Drug Deliv Rev, 6113: 1203-1213.
Hanafi-Bojd MY, Iranshahi M, Mosaffa F, Tehrani SO, Kalalinia F, Behravan J. 2011. Farnesiferol a from ferula persica and galbanic acid from ferula szowitsiana inhibit p-glycoprotein-mediated rhodamine efflux in breast cancer cell lines. Planta Med, 7714: 1590-1593.
Hanafi-Bojd MY, Jaafari MR, Ramezanian N, Abnous K, Malaekeh-Nikouei B. 2016. Co-delivery of epirubicin and siRNA using functionalized mesoporous silica nanoparticles enhances in vitro and in vivo drug efficacy. Curr Drug Deliv, 137: 1176-1182.
Hanafi-Bojd MY, Jaafari MR, Ramezanian N, Xue M, Amin M, Shahtahmassebi, Malaekeh-Nikouei B. 2015. Surface functionalized mesoporous silica nanoparticles as an effective carrier for epirubicin delivery to cancer cells. Eur J Pharm Biopharm, 89: 248-258.
Hu CM, Zhang L. 2012. Nanoparticle-based combination therapy toward overcoming drug resistance in cancer. Biochem Pharmacol, 838: 1104-1111.
Huq F, Yu JQ, Beale P, Chan C, Arzuman L, Nessa MU, Mazumder ME. 2014. Combinations of platinums and selected phytochemicals as a means of overcoming resistance in ovarian cancer. Anticancer Res, 341: 541-545.
Kasaian J, Iranshahy M, Iranshahi M. 2013. Synthesis, biosynthesis and biological activities of galbanic acid - A review. Pharm Biol, 52: 524-531
Kasaian J, Mosaffa F, Behravan J, Masullo M, Piacente S, Ghandadi M, Iranshahi M. 2015. Reversal of P-glycoprotein-mediated multidrug resistance in MCF-7/Adr cancer cells by sesquiterpene coumarins. Fitoterapia, 103: 149-154.
Kim KH, Lee HJ, Jeong SJ, Lee HJ, Lee EO, Kim HS, Zhang Y, Ryu SY, Lee MH, Lu J, Kim SH. 2011. Galbanic acid isolated from Ferula assafoetida exerts in vivo anti-tumor activity in association with anti-angiogenesis and anti-proliferation. Pharm Res, 283: 597-609.
Leibbrandt ME, Wolfgang GH. 1995. Differential toxicity of cisplatin, carboplatin, and CI-973 correlates with cellular platinum levels in rat renal cortical slices. Toxicol Appl Pharmacol, 1322: 245-252.
Oh BS, Shin EA, Jung JH, Jung DB, Kim B, Shim BS, Yazdi MC, Iranshahi M, Kim SH. 2015. Apoptotic effect of galbanic acid via activation of caspases and inhibition of Mcl1 in H460 nonsmall lung carcinoma cells. Phytother Res, 296: 844-849.
Salmon SE, Grogan TM, Miller T, Scheper R, Dalton WS. 1989. Prediction of doxorubicin resistance in vitro in myeloma, lymphoma, and breast cancer by P-glycoprotein staining. J Natl Cancer Inst, 819: 696-701.
Shoham J, Inbar M, Sachs L. 1970. Differential toxicity on normal and transformed cells in vitro and inhibition of tumour development in vivo by concanavalin A. Nature, 2275264: 1244-1246.
Strober W. 2015. Trypan Blue Exclusion Test of Cell Viability. Curr Protoc Immunol, 111: A3.b.1-3.
Teymouri M, Barati N, Pirro M, Sahebkar A. 2018. Biological and pharmacological evaluation of dimethoxycurcumin: A metabolically stable curcumin analogue with a promising therapeutic potential. J Cell Physiol, 2331: 124-140.
Teymouri M, Pirro M, Johnston TP, Sahebkar A. 2017. Curcumin as a multifaceted compound against human papilloma virus infection and cervical cancers: A review of chemistry, cellular, molecular, and preclinical features. BioFactors, 433: 331-346.
Zhao L, Wientjes MG, Au JL. 2004. Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses. Clin Cancer Res, 1023: 7994-8004.