Overexpression of Metallothionein Confers Resistance to Anticancer Drugs

Abstract

Resistance to antineoplastic agents is the major obstacle to curative therapy of cancer. Tumor cell lines with acquired resistance to the antineoplastic agent cis-diamminedichloroplatinum(II) overexpressed metallothionein and demonstrated cross-resistance to alkylating agents such as chlorambucil and melphalan. Human carcinoma cells that maintained high levels of metallothionein because of chronic exposure to heavy metals were resistant to cis-diamminedichloroplatinum(II), melphalan, and chlorambucil. Furthermore, cells transfected with bovine papilloma virus expression vectors containing DNA encoding human metallothionein-IIA were resistant to cis-diamminedichloroplatinum(II), melphalan, and chlorambucil but not to 5-fluorouracil or vincristine. Thus, overexpression of metallothionein represents one mechanism of resistance to a subset of clinically important anticancer drugs.

Monitoring metal ion flux in reactions of metallothionein and drug‐modified metallothionein by electrospray mass spectrometry

“…Specifically, the results show that alkylation at the level of even one adduct per MT molecule measurably increases the availability of zinc, thus producing a potential effect on the function of other zinc metalloproteins. The role proposed for the MT/thionein equilibrium in controlling its own transcription and synthesis (Czupryn et al, 1992;Maret, 1994;Vallee, 1995) has important implications for the mechanism of acquired drug resistance (Kelley et al, 1988;Yu et al, 1995;Zaia et al, 1996), because zinc made more biologically available by modification of MT may act to increase the rate of transcription of thionein. Increasing levels of thionein and MT would be expected to increase drug sequestration and inactivation.…”

“…MT synthesis has been found to be induced in some tumor cells exposed to alkylating chemotherapeutic agents (Kelley et al, 1988), and a causal role has been proposed for MT in the acquired drug resistance that interferes with long-term chemotherapy in many patients. Covalent sequestration is proposed as a mechanism, triggering induction of further synthesis (Yu et al, 1995;Zaia et al, 1996).…”

Reduced endocytosis and altered lysosome function in cisplatin-resistant cell lines

“…Intrinsic or acquired resistance of tumour cells to CP undermines its clinical effectiveness (Niedner et al, 2001). Mechanisms of resistance include decreased drug accumulation (Shen et al, 2000), changes in DNA repair proficiency (Fink et al, 1998;Zhen et al, 1992;Chu, 1994;Lai et al, 1995;Johnson et al, 1996), metallothionein (MT II) (Kelly et al, 1988;Kondo et al, 1995), glutathione-related enzymes (Moscow and Cowan, 1988;Godwin et al, 1992;Zaman et al, 1995), stress response proteins (Shen et al, 1995;Hettinga et al, 1997), proto-oncogenes or apoptosis-related genes, and cancer susceptibility genes (Fanidi et al, 1993;Lowe et al, 1993;DeFeudis et al, 1996;Husain et al, 1998;Moorehead and Singh, 2000). Protein kinases (PKs) like PKA and PKC have also been associated with CP-resistance (CP-r) and use of their specific inhibitors has been demonstrated to increase CP cytotoxicity in resistant tumour cells (Gosland et al, 1996).…”

New Isomeric Azine-Bridged Dinuclear Platinum(II) Complexes Circumvent Cross-Resistance to Cisplatin

“…[7][8][9][10][11] The resulting local conformational changes of DNA generated by platinum complexes might determine the antitumor activity of cisplatin. The mechanism of cisplatin-resistance seems to be multifactorial, and decreased drug accumulation, [12][13][14][15] increased intracellular detoxification, [16][17][18][19][20] and enhanced DNA repair 21 are known as three main factors. Assuming that the enhanced DNA repair is present as a certain mechanism of the drug resistance, a rational approach is to design a platinum compound that would bind to DNA in a different manner.…”