Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Gemini Curcumin Suppresses Proliferation of Ovarian Cancer OVCAR-3 Cells via Induction of Apoptosis

Author(s): Sonbol Ghaderi, Esmaeil Babaei*, Bashdar M. Hussen, Majid Mahdavi and Hewa J. Azeez

Volume 21 , Issue 6 , 2021

Published on: 07 August, 2020

Page: [775 - 781] Pages: 7

DOI: 10.2174/1871520620666200807223340

Price: $65


Background: Ovarian cancer has the highest mortality rate among gynecological malignancies. Despite recent advances in treatment, most patients still suffer from poor prognosis. Curcumin has shown highly cytotoxic effects against different types of cancer. However, its poor bioavailability restricts its clinical application. Gemini Curcumin (Gemini-Cur) has been developed to overcome this limitation.

Objective: Here, we aimed to unravel the inhibitory effect of Gemini-Cur in ovarian cancer.

Methods: OVCAR-3 cells were treated with free curcumin and Gemni-Cur in a time- and dose-dependent manner. Then, the anticancer activity was investigated by uptake kinetics, cellular viability and apoptotic assays. Furthermore, we evaluated the BAX/Bcl-2 expression ratio by real-time PCR and western blotting.

Results: Our data showed that gemini surfactant nanoparticles enhance the cellular uptake of curcumin compared to free curcumin (p<0.01). Regarding the growth inhibitory effect of nano-curcumin, the results demonstrated that Gemini-Cur suppresses the proliferation of OVCAR-3 cells through induction of apoptosis (p<0.001).

Conclusion: The results illustrate that Gemini-Cur nanoparticles have a great potential for developing novel therapeutics against ovarian cancer.

Keywords: Curcumin, gemini surfactant, ovarian cancer, apoptosis, OVCAR-3, BAX/Bcl-2.

Graphical Abstract
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[] [PMID: 25651787]
Thompson, L. World Health Organization classification of tumours: Pathology and genetics of head and neck tumours. Ear Nose Throat J., 2006, 85(2), 74.
[] [PMID: 16579185]
Sick, E.; Jeanne, A.; Schneider, C.; Dedieu, S.; Takeda, K.; Martiny, L. CD47 update: A multifaceted actor in the tumour microenvironment of potential therapeutic interest. Br. J. Pharmacol., 2012, 167(7), 1415-1430.
[] [PMID: 22774848]
Barclay, A.N.; Van den Berg, T.K. The interaction between Signal Regulatory Protein alpha (SIRPα) and CD47: Structure, function, and therapeutic target. Annu. Rev. Immunol., 2014, 32, 25-50.
[] [PMID: 24215318]
Sosale, N.G.; Spinler, K.R.; Alvey, C.; Discher, D.E. Macrophage engulfment of a cell or nanoparticle is regulated by unavoidable opsonization, a species-specific ‘Marker of Self’ CD47, and target physical properties. Curr. Opin. Immunol., 2015, 35, 107-112.
[] [PMID: 26172292]
Willingham, S.B.; Volkmer, J.P.; Gentles, A.J.; Sahoo, D.; Dalerba, P.; Mitra, S.S.; Wang, J.; Contreras-Trujillo, H.; Martin, R.; Cohen, J.D.; Lovelace, P.; Scheeren, F.A.; Chao, M.P.; Weiskopf, K.; Tang, C.; Volkmer, A.K.; Naik, T.J.; Storm, T.A.; Mosley, A.R.; Edris, B.; Schmid, S.M.; Sun, C.K.; Chua, M.S.; Murillo, O.; Rajendran, P.; Cha, A.C.; Chin, R.K.; Kim, D.; Adorno, M.; Raveh, T.; Tseng, D.; Jaiswal, S.; Enger, P.O.; Steinberg, G.K.; Li, G.; So, S.K.; Majeti, R.; Harsh, G.R.; van de Rijn, M.; Teng, N.N.; Sunwoo, J.B.; Alizadeh, A.A.; Clarke, M.F.; Weissman, I.L. The CD47-Signal Regulatory Protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc. Natl. Acad. Sci. USA, 2012, 109(17), 6662-6667.
[] [PMID: 22451913]
Yoshida, K.; Tsujimoto, H.; Matsumura, K.; Kinoshita, M.; Takahata, R.; Matsumoto, Y.; Hiraki, S.; Ono, S.; Seki, S.; Yamamoto, J.; Hase, K. CD47 is an adverse prognostic factor and a therapeutic target in gastric cancer. Cancer Med., 2015, 4(9), 1322-1333.
[] [PMID: 26077800]
Pan, Y.; Volkmer, J.P.; Mach, K.E.; Rouse, R.V.; Liu, J.J.; Sahoo, D.; Chang, T.C.; Metzner, T.J.; Kang, L.; van de Rijn, M.; Skinner, E.C.; Gambhir, S.S.; Weissman, I.L.; Liao, J.C. Endoscopic molecular imaging of human bladder cancer using a CD47 antibody. Sci. Transl. Med., 2014, 6(260)260ra148
[] [PMID: 25355698]
Amoyel, M.; Anderson, A.M.; Bach, E.A. JAK/STAT pathway dysregulation in tumors: A Drosophila perspective. Semin. Cell Dev. Biol., 2014, 28, 96-103.
[] [PMID: 24685611]
Geiger, J.L.; Grandis, J.R.; Bauman, J.E. The STAT3 pathway as a therapeutic target in head and neck cancer: Barriers and innovations. Oral Oncol., 2016, 56, 84-92.
[] [PMID: 26733183]
Banerjee, K.; Resat, H. Constitutive activation of STAT3 in breast cancer cells: A review. Int. J. Cancer, 2016, 138(11), 2570-2578.
[] [PMID: 26559373]
Dutta, P.; Sabri, N.; Li, J.; Li, W.X. Role of STAT3 in lung cancer. JAK-STAT, 2015, 3(4)e999503
[] [PMID: 26413424]
Lai, S.Y.; Johnson, F.M. Defining the role of the JAK-STAT pathway in head and neck and thoracic malignancies: Implications for future therapeutic approaches. Drug Resist. Updat., 2010, 13(3), 67-78.
[] [PMID: 20471303]
Kowshik, J.; Baba, A.B.; Giri, H.; Deepak Reddy, G.; Dixit, M.; Nagini, S. Astaxanthin inhibits JAK/STAT-3 signaling to abrogate cell proliferation, invasion and angiogenesis in a hamster model of oral cancer. PLoS One, 2014, 9(10)e109114
[] [PMID: 25296162]
Toledano, N.; Gur-Wahnon, D.; Ben-Yehuda, A.; Rachmilewitz, J. Novel CD47: SIRPα dependent mechanism for the activation of STAT3 in antigen-presenting cell. PLoS One, 2013, 8(9)e75595
[] [PMID: 24073274]
Ye, X.; Wang, X.; Lu, R.; Zhang, J.; Chen, X.; Zhou, G. CD47 as a potential prognostic marker for oral leukoplakia and oral squamous cell carcinoma. Oncol. Lett., 2018, 15(6), 9075-9080.
[] [PMID: 29805639]
Soto-Pantoja, D.R.; Stein, E.V.; Rogers, N.M.; Sharifi-Sanjani, M.; Isenberg, J.S.; Roberts, D.D. Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47. Expert Opin. Ther. Targets, 2013, 17(1), 89-103.
[] [PMID: 23101472]
Harrington, M. Blocking CD47 to stop tumor growth. Lab Anim. (NY), 2012, 41(5), 111.
[] [PMID: 22517079]
Kim, M.J.; Lee, J.C.; Lee, J.J.; Kim, S.; Lee, S.G.; Park, S.W.; Sung, M.W.; Heo, D.S. Association of CD47 with natural killer cell-mediated cytotoxicity of head-and-neck squamous cell carcinoma lines. Tumour Biol., 2008, 29(1), 28-34.
[] [PMID: 18497546]
Chan, K.S.; Espinosa, I.; Chao, M.; Wong, D.; Ailles, L.; Diehn, M.; Gill, H.; Presti, J., Jr; Chang, H.Y.; van de Rijn, M.; Shortliffe, L.; Weissman, I.L. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc. Natl. Acad. Sci. USA, 2009, 106(33), 14016-14021.
[] [PMID: 19666525]
Sick, E.; Boukhari, A.; Deramaudt, T.; Rondé, P.; Bucher, B.; André, P.; Gies, J.P.; Takeda, K. Activation of CD47 receptors causes proliferation of human astrocytoma but not normal astrocytes via an Akt-dependent pathway. Glia, 2011, 59(2), 308-319.
[] [PMID: 21125662]
Hatherley, D.; Lea, S.M.; Johnson, S.; Barclay, A.N. Polymorphisms in the human inhibitory signal-regulatory protein α do not affect binding to its ligand CD47. J. Biol. Chem., 2014, 289(14), 10024-10028.
[] [PMID: 24550402]
Kim, D.; Wang, J.; Willingham, S.B.; Martin, R.; Wernig, G.; Weissman, I.L. Anti-CD47 antibodies promote phagocytosis and inhibit the growth of human myeloma cells. Leukemia, 2012, 26(12), 2538-2545.
[] [PMID: 22648449]
Oldenborg, P.A. CD47: A cell surface glycoprotein which regulates multiple functions of hematopoietic cells in health and disease. ISRN Hematol., 2013, 2013614619
[] [PMID: 23401787]
Lv, Z.; Bian, Z.; Shi, L.; Niu, S.; Ha, B.; Tremblay, A.; Li, L.; Zhang, X.; Paluszynski, J.; Liu, M.; Zen, K.; Liu, Y. Loss of cell surface CD47 clustering formation and binding avidity to SIRPα facilitate apoptotic cell clearance by macrophages. J. Immunol., 2015, 195(2), 661-671.
[] [PMID: 26085683]
Uno, S.; Kinoshita, Y.; Azuma, Y.; Tsunenari, T.; Yoshimura, Y.; Iida, S.; Kikuchi, Y.; Yamada-Okabe, H.; Fukushima, N. Antitumor activity of a monoclonal antibody against CD47 in xenograft models of human leukemia. Oncol. Rep., 2007, 17(5), 1189-1194.
[] [PMID: 17390064]
Mateo, V.; Lagneaux, L.; Bron, D.; Biron, G.; Armant, M.; Delespesse, G.; Sarfati, M. CD47 ligation induces caspase-independent cell death in chronic lymphocytic leukemia. Nat. Med., 1999, 5(11), 1277-1284.
[] [PMID: 10545994]
Rivera, A.; Fu, X.; Tao, L.; Zhang, X. Expression of mouse CD47 on human cancer cells profoundly increases tumor metastasis in murine models. BMC Cancer, 2015, 15, 964.
[] [PMID: 26674012]
Wang, Y.; Xu, Z.; Guo, S.; Zhang, L.; Sharma, A.; Robertson, G.P.; Huang, L. Intravenous delivery of siRNA targeting CD47 effectively inhibits melanoma tumor growth and lung metastasis. Mol. Ther., 2013, 21(10), 1919-1929.
[] [PMID: 23774794]
Tan, M.; Zhu, L.; Zhuang, H.; Hao, Y.; Gao, S.; Liu, S.; Liu, Q.; Liu, D.; Liu, J.; Lin, B. Lewis Y antigen modified CD47 is an independent risk factor for poor prognosis and promotes early ovarian cancer metastasis. Am. J. Cancer Res., 2015, 5(9), 2777-2787.
[PMID: 26609483]
Zhang, Y.; Sime, W.; Juhas, M.; Sjölander, A. Crosstalk between colon cancer cells and macrophages via inflammatory mediators and CD47 promotes tumour cell migration. Eur. J. Cancer, 2013, 49(15), 3320-3334.
[] [PMID: 23810249]
Chao, M.P.; Tang, C.; Pachynski, R.K.; Chin, R.; Majeti, R.; Weissman, I.L. Extranodal dissemination of non-Hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy. Blood, 2011, 118(18), 4890-4901.
[] [PMID: 21828138]
Lo, J.; Lau, E.Y.; So, F.T.; Lu, P.; Chan, V.S.; Cheung, V.C.; Ching, R.H.; Cheng, B.Y.; Ma, M.K.; Ng, I.O.; Lee, T.K. Anti-CD47 antibody suppresses tumour growth and augments the effect of chemotherapy treatment in hepatocellular carcinoma. Liver Int., 2016, 36(5), 737-745.
[] [PMID: 26351778]
Xiao, Z.; Chung, H.; Banan, B.; Manning, P.T.; Ott, K.C.; Lin, S.; Capoccia, B.J.; Subramanian, V.; Hiebsch, R.R.; Upadhya, G.A.; Mohanakumar, T.; Frazier, W.A.; Lin, Y.; Chapman, W.C. Antibody mediated therapy targeting CD47 inhibits tumor progression of hepatocellular carcinoma. Cancer Lett., 2015, 360(2), 302-309.
[] [PMID: 25721088]
Ye, X.; Zhang, J.; Lu, R.; Zhou, G. Signal regulatory protein α associated with the progression of oral leukoplakia and oral squamous cell carcinoma regulates phenotype switch of macrophages. Oncotarget, 2016, 7(49), 81305-81321.
[] [PMID: 27793032]
Wang, T.; Niu, G.; Kortylewski, M.; Burdelya, L.; Shain, K.; Zhang, S.; Bhattacharya, R.; Gabrilovich, D.; Heller, R.; Coppola, D.; Dalton, W.; Jove, R.; Pardoll, D.; Yu, H. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat. Med., 2004, 10(1), 48-54.
[] [PMID: 14702634]
Mali, S.B. Review of STAT3 (Signal Transducers and Activators of Transcription) in head and neck cancer. Oral Oncol., 2015, 51(6), 565-569.
[] [PMID: 25817923]
Ferguson, S.D.; Srinivasan, V.M.; Heimberger, A.B. The role of STAT3 in tumor-mediated immune suppression. J. Neurooncol., 2015, 123(3), 385-394.
[] [PMID: 25700834]
Komohara, Y.; Horlad, H.; Ohnishi, K.; Ohta, K.; Makino, K.; Hondo, H.; Yamanaka, R.; Kajiwara, K.; Saito, T.; Kuratsu, J.; Takeya, M. M2 macrophage/microglial cells induce activation of Stat3 in primary central nervous system lymphoma. J. Clin. Exp. Hematop., 2011, 51(2), 93-99.
[] [PMID: 22104307]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy