Abstract
Tumor cell chemoresistance is a major challenge in cancer therapeutics. Major select metal-based drugs are potent anticancer mediators yet they exhibit adverse sideeffects and are efficient against limited types of malignancies. A need, therefore, arises for novel metallodrugs with improved efficacy and decreased toxicity. Enhancement of antitumor drugs based on anticancer metals is currently a very active research field, with considerable efforts having been made toward elucidating the mechanisms of immune action of complex metalloforms and optimizing their immunoregulatory bioactivity through appropriate synthetic structural modification(s) and encapsulation in suitable nanocarriers, thereby enhancing their selectivity, specificity, stability, and bioactivity. In that respect, comprehending the molecular factors involved in drug resistance and immune response may help us develop new approaches toward more promising chemotherapies, reducing the rate of relapse and overcoming chemoresistance. In this review, a) molecular immunerelated mechanisms in the tumor microenvironment, responsible for lower drug sensitivity and tumor relapse, along with b) strategies for reversing drug resistance and targeting immunosuppressive tumor networks, while concurrently optimizing the design of complex metalloforms bearing anti-tumor activity, are discussed in an effort to identify and overcome chemoresistance mechanisms for effective tumor immunotherapeutic approaches.
Keywords: Metallodrugs, molecular cancer therapeutics, immunosuppression, metastasis, chemoresistance, tumor infiltrating lymphocytes.
[1]
Komeda, S.; Casini, A. Next-generation anticancer metallodrugs. Curr. Top. Med. Chem., 2012, 12(3), 219-235.
[2]
Mjos, K.D.; Orvig, C. Metallodrugs in medicinal inorganic chemistry. Chem. Rev., 2014, 114(8), 4540-4563.
[3]
Tsave, O.; Petanidis, S.; Kioseoglou, E.; Yavropoulou, M.P.; Yovos, J.G.; Anestakis, D.; Tsepa, A.; Salifoglou, A. Role of Vanadium in Cellular and Molecular Immunology: Association with Immune-Related Inflammation and Pharmacotoxicology Mechanisms. Oxid. Med. Cell. Longev., 2016, 2016, 4013639.
[4]
Dilruba, S.; Kalayda, G.V. Platinum-based drugs: past, present and future. Cancer Chemother. Pharmacol., 2016, 77(6), 1103-1124.
[5]
Kachalaki, S.; Ebrahimi, M.; Mohamed Khosroshahi, L.; Mohammadinejad, S.; Baradaran, B. Cancer chemoresistance; biochemical and molecular aspects: a brief overview. Eur. J. Pharm. Sci., 2016, 89, 20-30.
[6]
Abdullah, L.N.; Chow, E.K. Mechanisms of chemoresistance in cancer stem cells. Clin. Transl. Med., 2013, 2(1), 3.
[7]
Holohan, C.; Van Schaeybroeck, S.; Longley, D.B.; Johnston, P.G. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer, 2013, 13(10), 714-726.
[8]
Kibria, G.; Hatakeyama, H.; Harashima, H. Cancer multidrug resistance: mechanisms involved and strategies for circumvention using a drug delivery system. Arch. Pharm. Res., 2014, 37(1), 4-15.
[9]
Burrell, R.A.; Swanton, C. Tumour heterogeneity and the evolution of polyclonal drug resistance. Mol. Oncol., 2014, 8(6), 1095-1111.
[10]
Türk, D.; Hall, M.D.; Chu, B.F.; Ludwig, J.A.; Fales, H.M.; Gottesman, M.M.; Szakács, G. Identification of compounds selectively killing multidrug-resistant cancer cells. Cancer Res., 2009, 69(21), 8293-8301.
[11]
Ganguly, A.; Chakraborty, P.; Banerjee, K.; Choudhuri, S.K. The role of a Schiff base scaffold, N-(2-hydroxy acetophenone) glycinate-in overcoming multidrug resistance in cancer. Eur. J. Pharm. Sci., 2014, 51, 96-109.
[12]
Hernanda, P.Y.; Pedroza-Gonzalez, A.; Sprengers, D.; Peppelenbosch, M.P.; Pan, Q. Multipotent mesenchymal stromal cells in liver cancer: implications for tumor biology and therapy. Biochim. Biophys. Acta, 2014, 1846(2), 439-445.
[13]
Muddineti, O.S.; Ghosh, B.; Biswas, S. Current trends in using polymer coated gold nanoparticles for cancer therapy. Int. J. Pharm., 2015, 484(1-2), 252-267.
[14]
Xiong, X.; Arvizo, R.R.; Saha, S.; Robertson, D.J.; McMeekin, S.; Bhattacharya, R.; Mukherjee, P. Sensitization of ovarian cancer cells to cisplatin by gold nanoparticles. Oncotarget, 2014, 5(15), 6453-6465.
[15]
Fan, J.X.; Zheng, D.W.; Rong, L.; Zhu, J.Y.; Hong, S.; Li, C.; Xu, Z.S.; Cheng, S.X.; Zhang, X.Z. Targeting epithelial-mesenchymal transition: Metal organic network nano-complexes for preventing tumor metastasis. Biomaterials, 2017, 139, 116-126.
[16]
Zhao, X.; Huang, Q.; Jin, Y. Gold nanorod delivery of LSD1 siRNA induces human mesenchymal stem cell differentiation. Mater. Sci. Eng. C, 2015, 54, 142-149.
[17]
Liu, Y.; Chen, C.; Qian, P.; Lu, X.; Sun, B.; Zhang, X.; Wang, L.; Gao, X.; Li, H.; Chen, Z.; Tang, J.; Zhang, W.; Dong, J.; Bai, R.; Lobie, P.E.; Wu, Q.; Liu, S.; Zhang, H.; Zhao, F.; Wicha, M.S.; Zhu, T.; Zhao, Y. Gd-metallofullerenol nanomaterial as non-toxic breast cancer stem cell-specific inhibitor. Nat. Commun., 2015, 6, 5988.
[18]
Geukes Foppen, M.H.; Donia, M.; Svane, I.M.; Haanen, J.B. Tumor-infiltrating lymphocytes for the treatment of metastatic cancer. Mol. Oncol., 2015, 9(10), 1918-1935.
[19]
Rei, M.; Pennington, D.J.; Silva-Santos, B. The emerging Protumor role of γδ T lymphocytes: implications for cancer immunotherapy. Cancer Res., 2015, 75(5), 798-802.
[20]
Montani, M.; Pazmay, G.V.B.; Hysi, A.; Lupidi, G.; Pettinari, R.; Gambini, V.; Tilio, M.; Marchetti, F.; Pettinari, C.; Ferraro, S.; Iezzi, M.; Marchini, C.; Amici, A. The water soluble ruthenium(II) organometallic compound [Ru(p-cymene)(bis(3,5 dimethylpyrazol-1-yl)methane)Cl]Cl suppresses triple negative breast cancer growth by inhibiting tumor infiltration of regulatory T cells. Pharmacol. Res., 2016, 107, 282-290.
[21]
Pacor, S.; Zorzet, S.; Cocchietto, M.; Bacac, M.; Vadori, M.; Turrin, C.; Gava, B.; Castellarin, A.; Sava, G. Intratumoral NAMI-A treatment triggers metastasis reduction, which correlates to CD44 regulation and tumor infiltrating lymphocyte recruitment. J. Pharmacol. Exp. Ther., 2004, 310(2), 737-744.
[22]
Crowe, A.; Jackaman, C.; Beddoes, K.M.; Ricciardo, B.; Nelson, D.J. Rapid copper acquisition by developing murine mesothelioma: decreasing bioavailable copper slows tumor growth, normalizes vessels and promotes T cell infiltration. PLoS One, 2013, 8(8), e73684.
[23]
Tsai, Y.S.; Chen, Y.H.; Cheng, P.C.; Tsai, H.T.; Shiau, A.L.; Tzai, T.S.; Wu, C.L. TGF-β1 conjugated to gold nanoparticles results in protein conformational changes and attenuates the biological function. Small, 2013, 9(12), 2119-2128.
[24]
Zhang, C.; Guan, Y.; Sun, Y.; Ai, D.; Guo, Q. Tumor heterogeneity and circulating tumor cells. Cancer Lett., 2016, 374(2), 216-223.
[25]
Wu, X.; Luo, L.; Yang, S.; Ma, X.; Li, Y.; Dong, C.; Tian, Y.; Zhang, L.; Shen, Z.; Wu, A. Improved SERS Nanoparticles for Direct Detection of Circulating Tumor Cells in the Blood. ACS Appl. Mater. Interfaces, 2015, 7(18), 9965-9971.
[26]
Jain, S.; Cohen, J.; Ward, M.M.; Kornhauser, N.; Chuang, E.; Cigler, T.; Moore, A.; Donovan, D.; Lam, C.; Cobham, M.V.; Schneider, S.; Hurtado Rúa, S.M.; Benkert, S.; Mathijsen Greenwood, C.; Zelkowitz, R.; Warren, J.D.; Lane, M.E.; Mittal, V.; Rafii, S.; Vahdat, L.T. Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse. Ann. Oncol., 2013, 24(6), 1491-1498.
[27]
Huang, X.; O’Connor, R.; Kwizera, E.A. Gold Nanoparticle Based Platforms for Circulating Cancer Marker Detection. Nanotheranostics, 2017, 1(1), 80-102.
[28]
Xing, Y.; Zhao, S.; Zhou, B.P.; Mi, J. Metabolic reprogramming of the tumour microenvironment. FEBS J., 2015, 282(20), 3892-3898.
[29]
Chen, Y.; Wang, Z.; Xu, M.; Wang, X.; Liu, R.; Liu, Q.; Zhang, Z.; Xia, T.; Zhao, J.; Jiang, G.; Xu, Y.; Liu, S. Nanosilver incurs an adaptive shunt of energy metabolism mode to glycolysis in tumor and nontumor cells. ACS Nano, 2014, 8(6), 5813-5825.
[30]
Yao, Y.; Lu, Y.; Chen, W.C.; Jiang, Y.; Cheng, T.; Ma, Y.; Lu, L.; Dai, W. Cobalt and nickel stabilize stem cell transcription factor OCT4 through modulating its sumoylation and ubiquitination. PLoS One, 2014, 9(1), e86620.
[31]
Chatterjee, S.; Mookerjee, A.; Basu, J.M.; Chakraborty, P.; Ganguly, A.; Adhikary, A.; Mukhopadhyay, D.; Ganguly, S.; Banerjee, R.; Ashraf, M.; Biswas, J.; Das, P.K.; Sa, G.; Chatterjee, M.; Das, T.; Choudhuri, S.K. A novel copper chelate modulates tumor associated macrophages to promote anti-tumor response of T cells. PLoS One, 2009, 4(9), e7048.
[32]
Karagiannis, G.S.; Poutahidis, T.; Erdman, S.E.; Kirsch, R.; Riddell, R.H.; Diamandis, E.P. Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol. Cancer Res., 2012, 10(11), 1403-1418.
[33]
Sack, M.; Alili, L.; Karaman, E.; Das, S.; Gupta, A.; Seal, S.; Brenneisen, P. Combination of conventional chemotherapeutics with redox-active cerium oxide nanoparticles--a novel aspect in cancer therapy. Mol. Cancer Ther., 2014, 13(7), 1740-1749.
[34]
Ng, C.T.; Yung, L.Y.; Swa, H.L.; Poh, R.W.; Gunaratne, J.; Bay, B.H. Altered protein expression profile associated with phenotypic changes in lung fibroblasts co-cultured with gold nanoparticle-treated small airway epithelial cells. Biomaterials, 2015, 39, 31-38.
[35]
Jain, R.K.; Martin, J.D.; Stylianopoulos, T. The role of mechanical forces in tumor growth and therapy. Annu. Rev. Biomed. Eng., 2014, 16, 321-346.
[36]
Crusz, S.M.; Balkwill, F.R. Inflammation and cancer: advances and new agents. Nat. Rev. Clin. Oncol., 2015, 12(10), 584-596.
[37]
Chua, A.C.; Klopcic, B.R.; Ho, D.S.; Fu, S.K.; Forrest, C.H.; Croft, K.D.; Olynyk, J.K.; Lawrance, I.C.; Trinder, D. Dietary iron enhances colonic inflammation and IL-6/IL-11-Stat3 signaling promoting colonic tumor development in mice. PLoS One, 2013, 8(11), e78850.
[38]
He, W.; Li, Y.; Tian, J.; Jiang, N.; Du, B.; Peng, Y. Optimized mixture of As, Cd and Pb induce mitochondria-mediated apoptosis in C6-glioma via astroglial activation, inflammation and P38-MAPK. Am. J. Cancer Res., 2015, 5(8), 2396-2408.
[39]
Wan, R.; Mo, Y.; Chien, S.; Li, Y.; Li, Y.; Tollerud, D.J.; Zhang, Q. The role of hypoxia inducible factor-1α in the increased MMP-2 and MMP-9 production by human monocytes exposed to nickel nanoparticles. Nanotoxicology, 2011, 5(4), 568-582.
[40]
Pyzer, A.R.; Cole, L.; Rosenblatt, J.; Avigan, D.E. Myeloid-derived suppressor cells as effectors of immune suppression in cancer. Int. J. Cancer, 2016, 139(9), 1915-1926.
[41]
Chakraborty, P.; Das, S.; Banerjee, K.; Sinha, A.; Roy, S.; Chatterjee, M.; Choudhuri, S.K. A copper chelate selectively triggers apoptosis in myeloid-derived suppressor cells in a drug-resistant tumor model and enhances antitumor immune response. Immunopharmacol. Immunotoxicol., 2014, 36(2), 165-175.
[42]
Das, S.; Banerjee, K.; Roy, S.; Majumder, S.; Chatterjee, M.; Majumdar, S.; Choudhuri, S.K. Mn complex-mediated enhancement of antitumor response through modulating myeloid-derived suppressor cells in drug-resistant tumor. In Vivo, 2014, 28(5), 909-918.
[43]
Younos, I.H.; Dafferner, A.J.; Gulen, D.; Britton, H.C.; Talmadge, J.E. Tumor regulation of myeloid-derived suppressor cell proliferation and trafficking. Int. Immunopharmacol., 2012, 13(3), 245-256.
[44]
Farrer, D.G.; Hueber, S.; Laiosa, M.D.; Eckles, K.G.; McCabe, M.J., Jr Reduction of myeloid suppressor cell derived nitric oxide provides a mechanistic basis of lead enhancement of alloreactive CD4(+) T cell proliferation. Toxicol. Appl. Pharmacol., 2008, 229(2), 135-145.
[45]
Tan, C.P.; Lu, Y.Y.; Ji, L.N.; Mao, Z.W. Metallomics insights into the programmed cell death induced by metal-based anticancer compounds. Metallomics, 2014, 6(5), 978-995.
[46]
Chatterjee, S.; Sarkar, S.; Bhattacharya, S. Toxic metals and autophagy. Chem. Res. Toxicol., 2014, 27(11), 1887-1900.
[47]
Lin, Y.X.; Gao, Y.J.; Wang, Y.; Qiao, Z.Y.; Fan, G.; Qiao, S.L.; Zhang, R.X.; Wang, L.; Wang, H. pH-Sensitive Polymeric Nanoparticles with Gold(I) Compound Payloads Synergistically Induce Cancer Cell Death through Modulation of Autophagy. Mol. Pharm., 2015, 12(8), 2869-2878.
[48]
Zhong, W.; Zhu, H.; Sheng, F.; Tian, Y.; Zhou, J.; Chen, Y.; Li, S.; Lin, J. Activation of the MAPK11/12/13/14 (p38 MAPK) pathway regulates the transcription of autophagy genes in response to oxidative stress induced by a novel copper complex in HeLa cells. Autophagy, 2014, 10(7), 1285-1300.
[49]
Laha, D.; Pramanik, A.; Maity, J.; Mukherjee, A.; Pramanik, P.; Laskar, A.; Karmakar, P. Interplay between autophagy and apoptosis mediated by copper oxide nanoparticles in human breast cancer cells MCF7. Biochim. Biophys. Acta, 2014, 1840(1), 1-9.
[50]
Whiteside, T.L. Exosomes and tumor-mediated immune suppression. J. Clin. Invest., 2016, 126(4), 1216-1223.
[51]
Alhasan, A.H.; Patel, P.C.; Choi, C.H.; Mirkin, C.A. Exosome encased spherical nucleic acid gold nanoparticle conjugates as potent microRNA regulation agents. Small, 2014, 10(1), 186-192.
[52]
Malhotra, H.; Sheokand, N.; Kumar, S.; Chauhan, A.S.; Kumar, M.; Jakhar, P.; Boradia, V.M.; Raje, C.I.; Raje, M. Exosomes: Tunable Nano Vehicles for Macromolecular Delivery of Transferrin and Lactoferrin to Specific Intracellular Compartment. J. Biomed. Nanotechnol., 2016, 12(5), 1101-1114.
[53]
De Stefani, D.; Patron, M.; Rizzuto, R. Structure and function of the mitochondrial calcium uniporter complex. Biochim. Biophys. Acta, 2015, 1853(9), 2006-2011.
[54]
Uzhachenko, R.; Shanker, A.; Yarbrough, W.G.; Ivanova, A.V. Mitochondria, calcium, and tumor suppressor Fus1: At the crossroad of cancer, inflammation, and autoimmunity. Oncotarget, 2015, 6(25), 20754-20772.
[55]
Hajrezaie, M.; Paydar, M.; Looi, C.Y.; Moghadamtousi, S.Z.; Hassandarvish, P.; Salga, M.S.; Karimian, H.; Shams, K.; Zahedifard, M.; Majid, N.A.; Ali, H.M.; Abdulla, M.A. Apoptotic effect of novel Schiff based CdCl2(C14H21N3O2) complex is mediated via activation of the mitochondrial pathway in colon cancer cells. Sci. Rep., 2015, 5, 9097.
[56]
Wang, Y.; Yang, F.; Zhang, H.X.; Zi, X.Y.; Pan, X.H.; Chen, F.; Luo, W.D.; Li, J.X.; Zhu, H.Y.; Hu, Y.P. Cuprous oxide nanoparticles inhibit the growth and metastasis of melanoma by targeting mitochondria. Cell Death Dis., 2013, 4, e783.
[57]
Bhana, S.; Wang, Y.; Huang, X. Nanotechnology for enrichment and detection of circulating tumor cells. Nanomedicine (Lond.), 2015, 10(12), 1973-1990.
[58]
Dreaden, E.C.; Alkilany, A.M.; Huang, X.; Murphy, C.J.; El-Sayed, M.A. The golden age: gold nanoparticles for biomedicine. Chem. Soc. Rev., 2012, 41(7), 2740-2779.
[59]
Roma-Rodrigues, C.; Raposo, L.R.; Cabral, R.; Paradinha, F.; Baptista, P.V.; Fernandes, A.R. Tumor Microenvironment Modulation via Gold Nanoparticles Targeting Malicious Exosomes: Implications for Cancer Diagnostics and Therapy. Int. J. Mol. Sci., 2017, 18(1), 162.
[60]
Luo, Y.H.; Chang, L.W.; Lin, P. Metal-Based Nanoparticles and the Immune System: Activation, Inflammation, and Potential Applications. BioMed Res. Int., 2015, 2015, 143720.
[61]
Sanchez-Cano, C.; Romero-Canelón, I.; Yang, Y.; Hands-Portman, I.J.; Bohic, S.; Cloetens, P.; Sadler, P.J. Synchrotron X-Ray Fluorescence Nanoprobe Reveals Target Sites for Organo-Osmium Complex in Human Ovarian Cancer Cells. Chemistry, 2017, 23(11), 2512-2516.
[62]
Nima, Z.A.; Mahmood, M.; Xu, Y.; Mustafa, T.; Watanabe, F.; Nedosekin, D.A.; Juratli, M.A.; Fahmi, T.; Galanzha, E.I.; Nolan, J.P.; Basnakian, A.G.; Zharov, V.P.; Biris, A.S. Circulating tumor cell identification by functionalized silver-gold nanorods with multicolor, super-enhanced SERS and photothermal resonances. Sci. Rep., 2014, 4, 4752.
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