Role of metal complexes in inhibition of cancer growth factors

Main Article Content

Saptarshi Mandal Subhajit Mahanty Soham Roy Dipankar Saha Supriti Mallick Soumitra Kumar Choudhuri Surajit Majumder

Abstract

Cancer is characterized by uncontrolled cell growth, representing a hallmark feature marked by sustained proliferation. This heightened proliferative capacity is primarily driven by the influence of growth factors. Scientific evidence suggests that growth factors play a crucial role in augmenting the transcription of specific proto-oncogenes, such as myc and fos. In the context of cancer development, these growth factors can be either produced by the cancer cells themselves or induce normal cells to release them through intricate signaling mechanisms. The functional diversity of growth factors encompasses various actions, but their predominant mode of operation is through the tyrosine kinase receptor pathway. Tyrosine kinase receptors, comprising integral membrane complexes with intrinsic kinase activity in their cytoplasmic domain, play a pivotal role in transducing signals initiated by the binding of specific growth factors (ligands). This binding event triggers the activation of the kinase function within the receptor, resulting in the phosphorylation of downstream targets on tyrosine and serine residues. Subsequently, this phosphorylation event recruits additional molecules into signaling cascades, amplifying the cellular response. Transition metals, such as Copper, Zinc, and Cobalt, integral to biological systems, play pivotal roles in normal physiological functions. However, dysregulation of these essential metals has been implicated in the pathogenesis of various disorders, including cancer. The narrative unfolds by elucidating the critical role of growth factors in cancer cell proliferation. Key growth factors, such as Transforming Growth Factor-β, Tumour Necrosis Factor-α and Insulin-like Growth Factors, are explored within the context of cancer progression. The intricate signaling pathways, particularly the Tyrosine Kinase Receptor pathway, are examined to understand how metal complexes may disrupt these pathways, impeding uncontrolled cell growth. Furthermore, this review provides an in-depth examination of medicinal inorganic chemistry, emphasizing the ability of transition metal complexes to form charged ions and induce hydrolysis reactions. The nuanced discussion underscores the necessity for precise dosages of metal-containing drugs to avoid undesirable toxicity, acknowledging the delicate balance required for optimal therapeutic responses. This comprehensive review delves into metal complexes of Cobalt, Copper, Zinc, and metal nanoparticles as promising inhibitors of cancer growth factors. By explicating the intricate interplay between metal complexes and growth factor pathways, this article contributes to the ongoing scientific exploration of novel and effective anticancer strategies.

Keywords: Growth Factors, Metal Complexes, Metal Nanoparticles, Copper, Zinc, Cancer

Article Details

How to Cite
MANDAL, Saptarshi et al. Role of metal complexes in inhibition of cancer growth factors. Medical Research Archives, [S.l.], v. 11, n. 12, jan. 2024. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/4996>. Date accessed: 15 may 2024. doi: https://doi.org/10.18103/mra.v11i12.4996.
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Research Articles

References

1. DeVita VT Jr, Chu E. A history of cancer chemotherapy. Cancer Res. 2008;68(21):8643-8653. doi:10.1158/0008-5472.CAN-07-6611

2. Hambley TW, Hait WN. Is anticancer drug development heading in the right direction? Cancer Res. 2009;69(4):1259-1262. doi:10.1158/0008-5472.CAN-08-3786

3. Neidle S, Thurston DE. Chemical approaches to the discovery and development of cancer therapies. Nat Rev Cancer. 2005;5(4):285-296. doi:10.1038/nrc1587

4. Orvig C, Abrams MJ. Medicinal inorganic chemistry: introduction. Chem Rev. 1999; 99(9):2201-2204. doi:10.1021/cr980419w

5. Yaman M, Kaya G, Yekeler H. Distribution of trace metal concentrations in paired cancerous and non-cancerous human stomach tissues. World J Gastroenterol. 2007; 13(4):612-618. doi:10.3748/wjg.v13.i4.612

6. Thompson KH, Orvig C. Boon and bane of metal ions in medicine. Science. 2003; 300(5621):936-939. doi:10.1126/science.1083004

7. Chen D, Milacic V, Frezza M, Dou QP. Metal complexes, their cellular targets and potential for cancer therapy. Curr Pharm Des. 2009;15(7):777-791. doi:10.2174/138161209787582183

8. Yan YK, Melchart M, Habtemariam A, Sadler PJ. Organometallic chemistry, biology and medicine: ruthenium arene anticancer complexes. Chem Commun (Camb). 2005;(38):4764-4776. doi:10.1039/b508531b

9. Weiss RB, Christian MC. New cisplatin analogues in development. A review [published correction appears in Drugs. 1993 Sep;46(3):377]. Drugs. 1993;46(3):360-377. doi:10.2165/00003495-199346030-00003

10. Criado JJ, Manzano JL, Rodríguez-Fernández E. New organotropic compounds. Synthesis, characterization and reactivity of Pt(II) and Au(III) complexes with bile acids: DNA interactions and 'in vitro' anticancer activity [published correction appears in J Inorg Biochem. 2005 Oct;99(10):2092]. J Inorg Biochem. 2003;96(2-3):311-320. doi:10.1016/s0162-0134(03)00240-x

11. Wong E, Giandomenico CM. Current status of platinum-based antitumor drugs. Chem Rev. 1999;99(9):2451-2466. doi:10.1021/cr980420v

12. Ho YP, Au-Yeung SC, To KK. Platinum-based anticancer agents: innovative design strategies and biological perspectives. Med Res Rev. 2003;23(5):633-655. doi:10.1002/med.10038

13. Daniel KG, Chen D, Orlu S, Cui QC, Miller FR, Dou QP. Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells. Breast Cancer Res. 2005;7(6):R897-R908. doi:10.1186/bcr1322

14. Milacic V, Chen D, Giovagnini L, Diez A, Fregona D, Dou QP. Pyrrolidine dithiocarbamate-zinc(II) and -copper(II) complexes induce apoptosis in tumor cells by inhibiting the proteasomal activity. Toxicol Appl Pharmacol. 2008;231(1):24-33. doi:10.1016/j.taap.2008.03.009

15. Milacic V, Chen D, Ronconi L, Landis-Piwowar KR, Fregona D, Dou QP. A novel anticancer gold(III) dithiocarbamate compound inhibits the activity of a purified 20S proteasome and 26S proteasome in human breast cancer cell cultures and xenografts. Cancer Res. 2006;66(21):10478-10486. doi:10.1158/0008-5472.CAN-06-3017

16. Hartinger CG, Jakupec MA, Zorbas-Seifried S, et al. KP1019, a new redox-active anticancer agent--preclinical development and results of a clinical phase I study in tumor patients. Chem Biodivers. 2008;5(10):2140-2155. doi:10.1002/cbdv.200890195

17. Hartinger CG, Zorbas-Seifried S, Jakupec MA, Kynast B, Zorbas H, Keppler BK. From bench to bedside--preclinical and early clinical development of the anticancer agent indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A). J Inorg Biochem. 2006;100(5-6):891-904. doi:10.1016/j.jinorgbio.2006.02.013

18. Bowen ML, Orvig C. 99m-Technetium carbohydrate conjugates as potential agents in molecular imaging. Chem Commun (Camb). 2008;(41):5077-5091. doi:10.1039/b809365b

19. Chen SC, Chou CK, Wong FH, Chang CM, Hu CP. Overexpression of epidermal growth factor and insulin-like growth factor-I receptors and autocrine stimulation in human esophageal carcinoma cells. Cancer Res. 1991;51(7):1898-1903.

20. Zare M, Moghanibashi M, Rastgar F. Growth factors, signal transduction pathways, and tumor suppressor genes in esophageal cancer. Esophageal Cancer. 2012:21-48. doi: 10.5772/30333

21. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5): 646-674. doi:10.1016/j.cell.2011.02.013

22. Sotiriou C, Neo SY, McShane LM, et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci U S A. 2003;100(18):10393-10398. doi:10.1073/pnas.1732912100

23. Bafico A, Aaronson SA. Classification of Growth Factors and Their Receptors. In: Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003. Available from: https://www.ncbi.nlm.nih.gov/books/NBK12423/

24. Sporn MB, Roberts AB. Peptide growth factors and inflammation, tissue repair, and cancer. J Clin Invest. 1986;78(2):329-332. doi:10.1172/JCI112580

25. Grotendorst GR, Seppä HE, Kleinman HK, Martin GR. Attachment of smooth muscle cells to collagen and their migration toward platelet-derived growth factor. Proc Natl Acad Sci U S A. 1981;78(6):3669-3672.
doi:10.1073/pnas.78.6.3669

26. Shimokado K, Raines EW, Madtes DK, Barrett TB, Benditt EP, Ross R. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell. 1985;43(1):277-286. doi:10.1016/0092-8674(85)90033-9

27. Carvalho I, Milanezi F, Martins A, Reis RM, Schmitt F. Overexpression of platelet-derived growth factor receptor alpha in breast cancer is associated with tumour progression. Breast Cancer Res. 2005;7(5):R788-R795. doi:10.1186/bcr1304

28. Najy AJ, Won JJ, Movilla LS, Kim HR. Differential tumorigenic potential and matriptase activation between PDGF B versus PDGF D in prostate cancer. Mol Cancer Res. 2012;10(8):1087-1097. doi:10.1158/1541-7786.MCR-12-0071

29. Ross R, Masuda J, Raines EW, et al. Localization of PDGF-B protein in macrophages in all phases of atherogenesis. Science. 1990;248(4958):1009-1012. doi:10.1126/science.2343305

30. Johnson RJ, Raines EW, Floege J, et al. Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor. J Exp Med. 1992;175(5):1413-1416. doi:10.1084/jem.175.5.1413

31. Lokker NA, Sullivan CM, Hollenbach SJ, Israel MA, Giese NA. Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells: evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res. 2002;62(13):3729-3735.

32. Tekmal RR, Ramachandra N, Gubba S, et al. Overexpression of int-5/aromatase in mammary glands of transgenic mice results in the induction of hyperplasia and nuclear abnormalities. Cancer Res. 1996;56(14):3180-3185.

33. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25(4):581-611. doi:10.1210/er.2003-0027

34. Roskoski R Jr. Vascular endothelial growth factor (VEGF) signaling in tumor progression. Crit Rev Oncol Hematol. 2007; 62(3):179-213. doi:10.1016/j.critrevonc.2007.01.006

35. Forsythe JA, Jiang BH, Iyer NV, et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16(9):4604-4613. doi:10.1128/MCB.16.9.4604

36. Alon T, Hemo I, Itin A, Pe'er J, Stone J, Keshet E. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med. 1995;1(10):1024-1028. doi:10.1038/nm1095-1024

37. Dvorak HF. Angiogenesis: update 2005. J Thromb Haemost. 2005;3(8):1835-1842. doi:10.1111/j.1538-7836.2005.01361.x

38. Roberts E, Cossigny DA, Quan GM. The role of vascular endothelial growth factor in metastatic prostate cancer to the skeleton. Prostate Cancer. 2013;2013:418340. doi:10.1155/2013/418340

39. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9(6):677-684. doi:10.1038/nm0603-677

40. Lawler J. Thrombospondin-1 as an endogenous inhibitor of angiogenesis and tumor growth. J Cell Mol Med. 2002;6(1):1-12. doi:10.1111/j.1582-4934.2002.tb00307.x

41. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004; 56(4):549-580. doi:10.1124/pr.56.4.3

42. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86(3):353-364. doi:10.1016/s0092-8674(00)80108-7

43. Goodsell DS. The molecular perspective: epidermal growth factor. Oncologist. 2003; 8(5):496-497. doi:10.1634/theoncologist.8-5-496

44. Groenen LC, Nice EC, Burgess AW. Structure-function relationships for the EGF/TGF-alpha family of mitogens. Growth Factors. 1994;11(4):235-257. doi:10.3109/08977199409010997

45. Sasaki T, Hiroki K, Yamashita Y. The role of epidermal growth factor receptor in cancer metastasis and microenvironment. Biomed Res Int. 2013;2013:546318. doi:10.1155/2013/546318

46. Shipley GD, Childs CB, Volkenant ME, Moses HL. Differential effects of epidermal growth factor, transforming growth factor, and insulin on DNA and protein synthesis and morphology in serum-free cultures of AKR-2B cells. Cancer Res. 1984;44(2):710-716.

47. Cooper JA, Hunter T. Similarities and differences between the effects of epidermal growth factor and Rous sarcoma virus. J Cell Biol. 1981;91(3 Pt 1):878-883. doi:10.1083/jcb.91.3.878

48. Müller R, Bravo R, Burckhardt J, Curran T. Induction of c-fos gene and protein by growth factors precedes activation of c-myc. Nature. 1984;312(5996):716-720. doi:10.1038/312716a0

49. Fisher PB, Bozzone JH, Weinstein IB. Tumor promoters and epidermal growth factor stimulate anchorage-independent growth of adenovirus-tranformed rat embryo cells. Cell. 1979;18(3):695-705. doi:10.1016/0092-8674(79)90124-7

50. Reynolds VH, Boehm FH, Cohen S. Enhancement of chemical carcinogenesis by an epidermal growth factor. Surg Forum. 1965;16:108-109.

51. Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 1999;79(4):1283-1316. doi:10.1152/physrev.1999.79.4.1283

52. Kwabi-Addo B, Ozen M, Ittmann M. The role of fibroblast growth factors and their receptors in prostate cancer. Endocr Relat Cancer. 2004;11(4):709-724. doi:10.1677/erc.1.00535

53. Folkman J, Shing Y. Angiogenesis. J Biol Chem. 1992;267(16):10931-10934.

54. Folkman J, Klagsbrun M. Angiogenic factors. Science. 1987;235(4787):442-447. doi:10.1126/science.2432664

55. Kamura S, Matsumoto Y, Fukushi JI, et al. Basic fibroblast growth factor in the bone microenvironment enhances cell motility and invasion of Ewing's sarcoma family of tumours by activating the FGFR1-PI3K-Rac1 pathway. Br J Cancer. 2010;103(3):370-381. doi:10.1038/sj.bjc.6605775

56. Dvorak P, Dvorakova D, Hampl A. Fibroblast growth factor signaling in embryonic and cancer stem cells. FEBS Lett. 2006;580(12):2869-2874. doi:10.1016/j.febslet.2006.01.095

57. Majka M, Janowska-Wieczorek A, Ratajczak J, et al. Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. Blood. 2001; 97(10):3075-3085. doi:10.1182/blood.v97.10.3075

58. Chesi M, Bergsagel PL, Kuehl WM. The enigma of ectopic expression of FGFR3 in multiple myeloma: a critical initiating event or just a target for mutational activation during tumor progression. Curr Opin Hematol. 2002;9(4):288-293. doi:10.1097/00062752-200207000-00005

59. Song S, Wientjes MG, Gan Y, Au JL. Fibroblast growth factors: an epigenetic mechanism of broad spectrum resistance to anticancer drugs. Proc Natl Acad Sci U S A. 2000;97(15):8658-8663. doi:10.1073/pnas.140210697

60. Dvorakova D, Krejci P, Mayer J, Fajkus J, Hampl A, Dvorak P. Changes in the expression of FGFR3 in patients with chronic myeloid leukaemia receiving transplants of allogeneic peripheral blood stem cells. Br J Haematol. 2001;113(3):832-835. doi:10.1046/j.1365-2141.2001.02829.x

61. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99-146. doi:10.1146/annurev.immunol.24.021605.090737

62. Yu H, Rohan T. Role of the insulin-like growth factor family in cancer development and progression. J Natl Cancer Inst. 2000;92(18):1472-1489. doi:10.1093/jnci/92.18.1472

63. Siddle K. Signalling by insulin and IGF receptors: supporting acts and new players. J Mol Endocrinol. 2011;47(1):R1-R10. Published 2011 Jun 17. doi:10.1530/JME-11-0022

64. Humphrey PA, Zhu X, Zarnegar R, et al. Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol. 1995;147(2):386-396.

65. Sonnenberg E, Meyer D, Weidner KM, Birchmeier C. Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development. J Cell Biol. 1993;123(1):223-235. doi:10.1083/jcb.123.1.223

66. Pasquale EB. Eph receptor signalling casts a wide net on cell behaviour [published correction appears in Nat Rev Mol Cell Biol. 2005 Jul;6(7):589]. Nat Rev Mol Cell Biol. 2005;6(6):462-475. doi:10.1038/nrm1662

67. Orvig C, Abrams MJ. Medicinal inorganic chemistry: introduction. Chem Rev. 1999; 99(9):2201-2204. doi:10.1021/cr980419w

68. Scott LE, Orvig C. Medicinal inorganic chemistry approaches to passivation and removal of aberrant metal ions in disease. Chem Rev. 2009;109(10):4885-4910. doi:10.1021/cr9000176

69. Haas KL, Franz KJ. Application of metal coordination chemistry to explore and manipulate cell biology. Chem Rev. 2009; 109(10):4921-4960. doi:10.1021/cr900134a

70. Zhao G, Lin H. Metal complexes with aromatic N-containing ligands as potential agents in cancer treatment. Curr Med Chem Anticancer Agents. 2005;5(2):137-147. doi:10.2174/1568011053174873

71. Jakupec MA, Galanski MS, Arion VB, Hartinger CG, Keppler BK. Antitumour metal compounds: more than theme and variations. Dalton Trans. 2008;(2):183-194. doi:10.1039/b712656p

72. Holm RH, Kennepohl P, Solomon EI. Structural and Functional Aspects of Metal Sites in Biology. Chem Rev. 1996;96(7):2239-2314. doi:10.1021/cr9500390

73. Mertz W. Essential trace metals: new definitions based on new paradigms. Nutr Rev. 1993;51(10):287-295. doi:10.1111/j.1753-4887.1993.tb03057.

74. Schwartz JA, Lium EK, Silverstein SJ. Herpes simplex virus type 1 entry is inhibited by the cobalt chelate complex CTC-96. J Virol. 2001;75(9):4117-4128. doi:10.1128/JVI.75.9.4117-4128.2001

75. Munteanu CR, Suntharalingam K. Advances in cobalt complexes as anticancer agents. Dalton Trans. 2015;44(31):13796-13808. doi:10.1039/c5dt02101d

76. Glasner H, Tshuva EY. A marked synergistic effect in antitumor activity of salan titanium(IV) complexes bearing two differently substituted aromatic rings. J Am Chem Soc. 2011;133(42):16812-16814. doi:10.1021/ja208219f

77. King AP, Gellineau HA, Ahn JE, MacMillan SN, Wilson JJ. Bis (thiosemicarbazone) Complexes of Cobalt(III). Synthesis, Characterization, and Anticancer Potential. Inorg Chem. 2017;56(11):6609-6623. doi:10.1021/acs.inorgchem.7b00710

78. Veeralakshmi S, Nehru S, Arunachalam S, Kumar P, Govindaraju M. Study of single and double chain surfactant–cobalt (III) complexes and their hydrophobicity, micelle formation, interaction with serum albumins and antibacterial activities. Inorg. Chem. Front. 2014;1:393-404. doi:10.1039/C4QI00018H

79. Veeralakshmi, S. et al. Single and double chain surfactant–cobalt (III) complexes: the impact of hydrophobicity on the interaction with calf thymus DNA, and their biological activities. RSC Adv. 2015;5:31746–31758. doi:10.1039/C5RA02763B

80. Choudhuri SK, Dutta P, Majumder S, Panda G. A novel cobalt complex useful for reversal of drug resistance and the preparation thereof. Patent application number: 1210/DEL/2004, dated: 30/06/2004, International Classification 7: A 61 K 31/28. Published in The Patent Office Journal 16/09/2005, pp. 21868. https://search.ipindia.gov.in/IPOJournal/Journal/ViewJournal

81. Skrajnowska D, Bobrowska-Korczak B. Role of Zinc in Immune System and Anti-Cancer Defense Mechanisms. Nutrients. 2019;11(10):2273. Published 2019 Sep 22. doi:10.3390/nu11102273

82. Nishihara M, Ogura H, Ueda N, et al. IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state. Int Immunol. 2007;19(6):695-702. doi:10.1093/intimm/dxm045

83. Kitabayashi C, Fukada T, Kanamoto M, et al. Zinc suppresses Th17 development via inhibition of STAT3 activation. Int Immunol. 2010;22(5):375-386. doi:10.1093/intimm/dxq017

84. Skrajnowska D, Bobrowska-Korczak B. Role of Zinc in Immune System and Anti-Cancer Defense Mechanisms. Nutrients. 2019;11(10):2273. Published 2019 Sep 22. doi:10.3390/nu11102273

85. Supasai S, Aimo L, Adamo AM, Mackenzie GG, Oteiza PI. Zinc deficiency affects the STAT1/3 signaling pathways in part through redox-mediated mechanisms. Redox Biol. 2017;11:469-481. doi:10.1016/j.redox.2016.12.027

86. Arriaga JM, Bravo IA, Bruno L, et al. Combined metallothioneins and p53 proteins expression as a prognostic marker in patients with Dukes stage B and C colorectal cancer. Hum Pathol. 2012;43(10):1695-1703. doi:10.1016/j.humpath.2011.12.014

87. Puca R, Nardinocchi L, Bossi G, et al. Restoring wtp53 activity in HIPK2 depleted MCF7 cells by modulating metallothionein and zinc. Exp Cell Res. 2009;315(1):67-75. doi:10.1016/j.yexcr.2008.10.018

88. Méplan C, Richard MJ, Hainaut P. Metalloregulation of the tumor suppressor protein p53: zinc mediates the renaturation of p53 after exposure to metal chelators in vitro and in intact cells. Oncogene. 2000;19(46): 5227-5236. doi:10.1038/sj.onc.1203907

89. Butler JS, Loh SN. Zn(2+)-dependent misfolding of the p53 DNA binding domain. Biochemistry. 2007;46(10):2630-2639. doi:10.1021/bi062106y

90. Chimienti F, Seve M, Richard S, Mathieu J, Favier A. Role of cellular zinc in programmed cell death: temporal relationship between zinc depletion, activation of caspases, and cleavage of Sp family transcription factors. Biochem Pharmacol. 2001;62(1):51-62. doi:10.1016/s0006-2952(01)00624-4

91. Dutsch-Wicherek M, Sikora J, Tomaszewska R. The possible biological role of metallothionein in apoptosis. Front Biosci. 2008;13:4029-4038. Published 2008 May 1. doi:10.2741/2991

92. Ho E. Zinc deficiency, DNA damage and cancer risk. J Nutr Biochem. 2004;15(10):572-578. doi:10.1016/j.jnutbio.2004.07.005

93. Cho Y, Gorina S, Jeffrey PD, Pavletich NP. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science. 1994;265(5170):346-355. doi:10.1126/science.8023157

94. Hainaut P, Milner J. A structural role for metal ions in the "wild-type" conformation of the tumor suppressor protein p53. Cancer Res. 1993;53(8):1739-1742.

95. Pavletich NP, Pabo CO. Crystal structure of a five-finger GLI-DNA complex: new perspectives on zinc fingers. Science. 1993;261(5129):1701-1707. doi:10.1126/science.8378770

96. Garufi A, Trisciuoglio D, Porru M, et al. A fluorescent curcumin-based Zn(II)-complex reactivates mutant (R175H and R273H) p53 in cancer cells. J Exp Clin Cancer Res. 2013;32(1):72. Published 2013 Oct 7. doi:10.1186/1756-9966-32-72

97. Yousef TA, Abu El-Reash GM, Al-Jahdali M, El-Rakhawy el-BR. Synthesis, spectral characterization and biological evaluation of Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) complexes with thiosemicarbazone ending by pyrazole and pyridyl rings. Spectrochim Acta A Mol Biomol Spectrosc. 2014;129:163-172. doi:10.1016/j.saa.2014.02.184

98. Tyagi P, Tyagi M, Agrawal S, Chandra S, Ojha H, Pathak M. Synthesis, characterization of 1,2,4-triazole Schiff base derived 3d-metal complexes: Induces cytotoxicity in HepG2, MCF-7 cell line, BSA binding fluorescence and DFT study. Spectrochim Acta A Mol Biomol Spectrosc. 2017;171:246-257. doi:10.1016/j.saa.2016.08.008

99. Mazumdar ZH, Sharma D, Mukherjee A, et al. meso-Thiophenium Porphyrins and Their Zn(II) Complexes: A New Category of Cationic Photosensitizers. ACS Med Chem Lett. 2020;11(10):2041-2047. Published 2020 Sep 10. doi:10.1021/acsmedchemlett.0c00266

100. Michalczyk K, Cymbaluk-Płoska A. The Role of Zinc and Copper in Gynecological Malignancies. Nutrients. 2020;12(12):3732. Published 2020 Dec 3. doi:10.3390/nu12123732

101. Ancona A, Dumontel B, Garino N, et al. Lipid-Coated Zinc Oxide Nanoparticles as Innovative ROS-Generators for Photodynamic Therapy in Cancer Cells. Nanomaterials (Basel). 2018;8(3):143. Published 2018 Mar 2. doi:10.3390/nano8030143

102. Zhou XQ, Meng LB, Huang Q, et al. Synthesis and in vitro anticancer activity of zinc(II) phthalocyanines conjugated with coumarin derivatives for dual photodynamic and chemotherapy. Chem Med Chem. 2015; 10(2):304-311. doi:10.1002/cmdc.201402401

103. Zhang FL, Huang Q, Liu JY, Huang MD, Xue JP. Molecular-target-based anticancer photosensitizer: synthesis and in vitro photodynamic activity of erlotinib-zinc(II) phthalocyanine conjugates. Chem Med Chem. 2015;10(2):312-320. doi:10.1002/cmdc.201402373

104. Mahanty S, Saha D, Choudhuri SK, Majumder S. Role of metal complexes in oxidative stress and ROS generation leading to cancer. Medical Research Archives. 2023;11(11):Web. 29 Dec. 23. doi:10.18103/mra.v11i11.4661

105. Iljin K, Ketola K, Vainio P, et al. High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth. Clin Cancer Res. 2009;15(19):6070-6078. doi:10.1158/1078-0432.CCR-09-1035

106. Duan X, Xiao J, Yin Q, et al. Multi-targeted inhibition of tumor growth and lung metastasis by redox-sensitive shell crosslinked micelles loading disulfiram. Nanotechnology. 2014;25(12):125102. doi:10.1088/0957-4484/25/12/125102

107. Liu P, Wang Z, Brown S, et al. Liposome encapsulated Disulfiram inhibits NFκB pathway and targets breast cancer stem cells in vitro and in vivo. Oncotarget. 2014;5(17): 7471-7485. doi:10.18632/oncotarget.2166

108. Wang Z, Tan J, McConville C, et al. Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells. Nanomedicine. 2017;13(2):641-657. doi:10.1016/j.nano.2016.08.001

109. He H, Markoutsa E, Li J, Xu P. Repurposing disulfiram for cancer therapy via targeted nanotechnology through enhanced tumor mass penetration and disassembly. Acta Biomater. 2018;68:113-124. doi:10.1016/j.actbio.2017.12.023

110. Buac D, Schmitt S, Ventro G, Kona FR, Dou QP. Dithiocarbamate-based coordination compounds as potent proteasome inhibitors in human cancer cells. Mini Rev Med Chem. 2012;12(12):1193-1201. doi:10.2174/138955712802762040

111. Yip NC, Fombon IS, Liu P, et al. Disulfiram modulated ROS-MAPK and NFκB pathways and targeted breast cancer cells with cancer stem cell-like properties. Br J Cancer. 2011;104(10):1564-1574. doi:10.1038/bjc.2011.126

112. Liu P, Brown S, Goktug T, et al. Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells. Br J Cancer. 2012; 107(9):1488-1497. doi:10.1038/bjc.2012.442

113. Huang R, Rofstad EK. Cancer stem cells (CSCs), cervical CSCs and targeted therapies. Oncotarget. 2017;8(21):35351-35367. doi:10.18632/oncotarget.10169

114. Xu B, Wang S, Li R, et al. Disulfiram/copper selectively eradicates AML leukemia stem cells in vitro and in vivo by simultaneous induction of ROS-JNK and inhibition of NF-κB and Nrf2. Cell Death Dis. 2017;8(5):e2797. Published 2017 May 18. doi:10.1038/cddis.2017.176

115. Lewis DJ, Deshmukh P, Tedstone AA, Tuna F, O'Brien P. On the interaction of copper(II) with disulfiram. Chem Commun (Camb). 2014;50(87):13334-13337. doi:10.1039/c4cc04767b

116. Lu X, Lin B, Xu N, Huang H, Wang Y, Lin JM. Evaluation of the accumulation of disulfiram and its copper complex in A549 cells using mass spectrometry. Talanta. 2020; 211:120732. doi:10.1016/j.talanta.2020.120732

117. Yoshino H, Yamada Y, Enokida H, et al. Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma. PLoS One. 2020;15(7): e0236119. Published 2020 Jul 15. doi:10.1371/journal.pone.0236119

118. Tawari PE, Wang Z, Najlah M, et al. The cytotoxic mechanisms of disulfiram and copper(ii) in cancer cells. Toxicol Res (Camb). 2015;4(6):1439-1442. doi:10.1039/c5tx00210a

119. Majera D, Skrott Z, Chroma K, Merchut-Maya JM, Mistrik M, Bartek J. Targeting the NPL4 Adaptor of p97/VCP Segregase by Disulfiram as an Emerging Cancer Vulnerability Evokes Replication Stress and DNA Damage while Silencing the ATR Pathway. Cells. 2020;9(2):469. Published 2020 Feb 18. doi:10.3390/cells9020469

120. Guo X, Xu B, Pandey S, et al. Disulfiram/copper complex inhibiting NFkappaB activity and potentiating cytotoxic effect of gemcitabine on colon and breast cancer cell lines. Cancer Lett. 2010;290(1): 104-113. doi:10.1016/j.canlet.2009.09.002

121. Cvek B, Dvorak Z. The value of proteasome inhibition in cancer. Can the old drug, disulfiram, have a bright new future as a novel proteasome inhibitor? Drug Discov Today. 2008;13(15-16):716-722. doi:10.1016/j.drudis.2008.05.003

122. Verzella D, Pescatore A, Capece D, et al. Life, death, and autophagy in cancer: NF-κB turns up everywhere. Cell Death Dis. 2020;11(3):210. Published 2020 Mar 30. doi:10.1038/s41419-020-2399-y

123. Wang W, McLeod HL, Cassidy J. Disulfiram-mediated inhibition of NF-kappaB activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. Int J Cancer. 2003;104(4):504-511. doi:10.1002/ijc.10972

124. Jackson B, Brocker C, Thompson DC, et al. Update on the aldehyde dehydrogenase gene (ALDH) superfamily. Hum Genomics. 2011;5(4):283-303. doi:10.1186/1479-7364-5-4-283

125. Liu P, Kumar IS, Brown S, et al. Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells. Br J Cancer. 2013;109(7):1876-1885. doi:10.1038/bjc.2013.534

126. Yang Z, Guo F, Albers AE, Sehouli J, Kaufmann AM. Disulfiram modulates ROS accumulation and overcomes synergistically cisplatin resistance in breast cancer cell lines. Biomed Pharmacother. 2019;113:108727. doi:10.1016/j.biopha.2019.108727

127. Schmidtova S, Kalavska K, Gercakova K, et al. Disulfiram Overcomes Cisplatin Resistance in Human Embryonal Carcinoma Cells. Cancers (Basel). 2019;11(9):1224. Published 2019 Aug 22. doi:10.3390/cancers11091224

128. Guo F, Yang Z, Kulbe H, Albers AE, Sehouli J, Kaufmann AM. Inhibitory effect on ovarian cancer ALDH+ stem-like cells by Disulfiram and Copper treatment through ALDH and ROS modulation. Biomed Pharmacother. 2019;118:109371. doi:10.1016/j.biopha.2019.109371

129. Xu Y, Zhou Q, Feng X, et al. Disulfiram/copper markedly induced myeloma cell apoptosis through activation of JNK and intrinsic and extrinsic apoptosis pathways. Biomed Pharmacother. 2020;126: 110048. doi:10.1016/j.biopha.2020.110048

130. Wall L, Burke F, Barton C, Smyth J, Balkwill F. IFN-gamma induces apoptosis in ovarian cancer cells in vivo and in vitro. Clin Cancer Res. 2003;9(7):2487-2496.

131. North RJ. Down-regulation of the antitumor immune response. Adv Cancer Res. 1985;45:1-43. doi:10.1016/s0065-230x(08)60265-1

132. Finke J, Ferrone S, Frey A, Mufson A, Ochoa A. Where have all the T cells gone? Mechanisms of immune evasion by tumors. Immunol Today. 1999;20(4):158-160. doi:10.1016/s0167-5699(98)01435-2

133. Gamero AM, Ussery D, Reintgen DS, Puleo CA, Djeu JY. Interleukin 15 induction of lymphokine-activated killer cell function against autologous tumor cells in melanoma patient lymphocytes by a CD18-dependent, perforin-related mechanism. Cancer Res. 1995;55(21):4988-4994.

134. Ochsenbein AF, Sierro S, Odermatt B, et al. Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction [published correction appears in Nature 2001 Sep 13;413(6852):183]. Nature. 2001;411(6841):1058-1064. doi:10.1038/35082583

135. Utaisincharoen P, Tangthawornchaikul N, Ubol S, Chaisuriya P, Sirisinha S. TNF-alpha induces caspase 3 (CPP 32) dependent apoptosis in human cholangiocarcinoma cell line. Southeast Asian J Trop Med Public Health. 2000;31 Suppl 1:167-170.

136. Yonekura N, Yokota S, Yonekura K, et al. Interferon-gamma downregulates Hsp27 expression and suppresses the negative regulation of cell death in oral squamous cell carcinoma lines. Cell Death Differ. 2003; 10(3):313-322. doi:10.1038/sj.cdd.4401169

137. Rayman P, Wesa AK, Richmond AL, et al. Effect of renal cell carcinomas on the development of type 1 T-cell responses. Clin Cancer Res. 2004;10(18 Pt 2):6360S-6S. doi:10.1158/1078-0432.CCR-050011

138. Van Ginderachter JA, Liu Y, Geldhof AB, et al. B7-1, IFN gamma and anti-CTLA-4 co-operate to prevent T-cell tolerization during immunotherapy against a murine T-lymphoma. Int J Cancer. 2000;87(4):539-547.

139. Herskind C, Fleckenstein K, Lohr J, Li CY, Wenz F, Lohr F. Antitumorale Wirkung von Interferonen und Interleukinen in Kombination mit Strahlentherapie. Teil I: Immunologische Grundlagen [Antitumoral action of interferons and interleukins in combination with radiotherapy. Part I: immunologic basis]. Strahlenther Onkol. 2004;180(4):187-193. doi:10.1007/s00066-004-9119-x

140. Mookerjee A, Mookerjee Basu J, Dutta P, et al. Overcoming drug-resistant cancer by a newly developed copper chelate through host-protective cytokine-mediated apoptosis. Clin Cancer Res. 2006;12(14 Pt 1):4339-4349. doi:10.1158/1078-0432.CCR-06-0001

141. Gu YQ, Zhong YJ, Hu MQ, et al. Terpyridine copper(II) complexes as potential anticancer agents by inhibiting cell proliferation, blocking the cell cycle and inducing apoptosis in BEL-7402 cells. Dalton Trans. 2022;51(5):1968-1978. Published 2022 Feb 1. doi:10.1039/d1dt02988f

142. Basak D, Arrighi S, Darwiche Y, Deb S. Comparison of Anticancer Drug Toxicities: Paradigm Shift in Adverse Effect Profile. Life (Basel). 2021;12(1):48. Published 2021 Dec 29. doi:10.3390/life12010048

143. Nussinov R, Tsai CJ, Jang H. Anticancer drug resistance: An update and perspective. Drug Resist Updat. 2021;59:100796. doi:10.1016/j.drup.2021.100796

144. Gomes HIO, Martins CSM, Prior JAV. Silver Nanoparticles as Carriers of Anticancer Drugs for Efficient Target Treatment of Cancer Cells. Nanomaterials (Basel). 2021;11(4):964. Published 2021 Apr 9. doi:10.3390/nano11040964

145. Matthews HK, Bertoli C, de Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol. 2022;23(1):74-88. doi:10.1038/s41580-021-00404-3

146. Sun Y, Liu Y, Ma X, Hu H. The Influence of Cell Cycle Regulation on Chemotherapy. Int J Mol Sci. 2021;22(13):6923. Published 2021 Jun 28. doi:10.3390/ijms22136923

147. Vermeulen K, Van Bockstaele DR, Berneman ZN. The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif. 2003;36(3):131-149. doi:10.1046/j.1365-2184.2003.00266.x

148. Oladipo AO, Unuofin JO, Lebelo SL, Msagati TAM. Phytochemical-Stabilized Platinum-Decorated Silver Nanocubes INHIBIT Adenocarcinoma Cells and Enhance Antioxidant Effects by Promoting Apoptosis via Cell Cycle Arrest. Pharmaceutics. 2022;14(11):2541. Published 2022 Nov 21. doi:10.3390/pharmaceutics14112541

149. Mokhtar FA, Selim NM, Elhawary SS, et al. Green Biosynthesis of Silver Nanoparticles Using Annona glabra and Annona squamosal Extracts with Antimicrobial, Anticancer, Apoptosis Potentials, Assisted by In Silico Modeling, and Metabolic Profiling. Pharmaceuticals (Basel). 2022;15(11):1354. Published 2022 Nov 2. doi:10.3390/ph15111354

150. Black AR, Black JD. Protein kinase C signaling and cell cycle regulation. Front Immunol. 2013;3:423. Published 2013 Jan 17. doi:10.3389/fimmu.2012.00423

151. De Matteis V, Malvindi MA, Galeone A, et al. Negligible particle-specific toxicity mechanism of silver nanoparticles: the role of Ag+ ion release in the cytosol. Nanomedicine. 2015; 11(3):731-739. doi:10.1016/j.nano.2014.11.002

152. Bin-Jumah M, Al-Abdan M, Albasher G, Alarifi S. Effects of Green Silver Nanoparticles on Apoptosis and Oxidative Stress in Normal and Cancerous Human Hepatic Cells in vitro. Int J Nanomedicine. 2020;15:1537-1548. Published 2020 Mar 9. doi:10.2147/IJN.S239861

153. Ahmadian E, Dizaj SM, Rahimpour E, et al. Effect of silver nanoparticles in the induction of apoptosis on human hepatocellular carcinoma (HepG2) cell line. Mater Sci Eng C Mater Biol Appl. 2018; 93:465-471. doi:10.1016/j.msec.2018.08.027

154. Haase H, Fahmi A, Mahltig B. Impact of silver nanoparticles and silver ions on innate immune cells. J Biomed Nanotechnol. 2014; 10(6):1146-1156. doi:10.1166/jbn.2014.1784

155. Mendonça MCP, Ferreira LB, Rizoli C, et al. N-Acetylcysteine reverses silver nanoparticle intoxication in rats. Nanotoxicology. 2019; 13(3):326-338. doi:10.1080/17435390.2018.1544302

156. Valenzuela-Salas LM, Girón-Vázquez NG, García-Ramos JC, et al. Antiproliferative and Antitumour Effect of Nongenotoxic Silver Nanoparticles on Melanoma Models. Oxid Med Cell Longev. 2019;2019:4528241. Published 2019 Jul 25. doi:10.1155/2019/4528241

157. Gliga AR, Skoglund S, Wallinder IO, Fadeel B, Karlsson HL. Size-dependent cytotoxicity of silver nanoparticles in human lung cells: the role of cellular uptake, agglomeration and Ag release. Part Fibre Toxicol. 2014;11:11. Published 2014 Feb 17. doi:10.1186/1743-8977-11-11

158. Kullmann F, Hollerbach S, Dollinger MM, et al. Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study. Br J Cancer. 2009;100(7):1032-1036. doi:10.1038/sj.bjc.6604983

159. Patra CR, Bhattacharya R, Wang E, et al. Targeted delivery of gemcitabine to pancreatic adenocarcinoma using cetuximab as a targeting agent. Cancer Res. 2008;68(6):1970-1978. doi:10.1158/0008-5472.CAN-07-6102

160. Jiang W, Kim BY, Rutka JT, Chan WC. Nanoparticle-mediated cellular response is size-dependent. Nat Nanotechnol. 2008; 3(3):145-150. doi:10.1038/nnano.2008.30

161. Sun L, Liu Y, Yang N, et al. Gold nanoparticles inhibit tumor growth via targeting the Warburg effect in a c-Myc-dependent way. Acta Biomater. 2023;158: 583-598. doi:10.1016/j.actbio.2022.12.054

162. Zhang A, Nakanishi J. Improved anti-cancer effect of epidermal growth factor-gold nanoparticle conjugates by protein orientation through site-specific mutagenesis. Sci Technol Adv Mater. 2021;22(1):616-626. Published 2021 Sep 6. doi:10.1080/14686996.2021.1944783