Combining carbonic anhydrase and thioredoxin reductase inhibitory motifs within a single molecule dramatically increases its cytotoxicity

Abstract

A hypothesis that simultaneous targeting cancer-related carbonic anhydrase hCA IX and hCA XII isoforms (whose overexpression is a cancer cell's defence mechanism against hypoxia) along with thioredoxin reductase (overexpressed in cancers as a defence against oxidative stress) may lead to synergistic antiproliferative effects was confirmed by testing combinations of the two inhibitor classes against pancreatic cancer cells (PANC-1). Combining both pharmacophoric motifs within one molecule led to a sharp increase of cytotoxicity. This preliminary observation sets the ground for a fundamentally new approach to anticancer agent design.

Thioredoxin-dependent system. Application of inhibitors

“…Therefore, the search for other TrxR inhibitors that will simultaneously inhibit the action of other pro-survival enzymes in relation to cancer cells is ongoing. Such a group of compounds includes the sulfocoumarins 93 and other Michael acceptors which inhibit both thioredoxin reductase and carbonic anhydrase 94 . The presence of electron withdrawing groups in their structures makes them act as Michael acceptors and thus have the ability to inhibit the activity of TrxR 93 .…”

“…A similar effect was observed for a synthetic compound that contains both the Michael acceptor group (responsible for the inhibition of TrxR) and the motif responsible for inhibiting carbonic anhydrase, which is very important in the process of carcinogenesis, because carbonic anhydrase protects cancer cells against acidification and hypoxia, preventing them death. This "hybrid" exhibits significant cytotoxicity to the pancreatic cancer cell line (PANC-1) compared to co-administered combinations of TrxR inhibitors and carbonic anhydrase inhibitors 94 . Consequently, due to the efficacy and preference for cancer cells, the synthesis and further research on Michael acceptors indicate the possible emergence of a compound effective in the treatment of highly multi-drug resistant cancers ( Table 2 ).…”

Multitargeting approaches involving carbonic anhydrase inhibitors: hybrid drugs against a variety of disorders

“…Some of the most widely used anticancer drugs nowadays are the tyrosine kinase inhibitors and the tubulin polymerisation inhibitors, with many new representatives of these classes being launched each year 69 . Thus, in this paragraph I will examine a set of hybridisation approaches which involve CAIs and several other, rather heterogeneous classes of antitumor agents, among which the epidermal growth factor receptor (EGFR) antagonists (this protein has kinase activity) 70 , the 15-lipoxygenase (15-LOX)/COX-2 (multitargeting of tree different proteins) inhibitors 71 , the telomerase inhibitors 72 , the P-glycoprotein (P-gp) inhibitors 73 , and the thioredoxin inhibitors 74 , 75 .…”

“…Recently, Krasavin et al. 74 , 75 proposed another interesting multitargeting approach of two enzymes involved in cancerogenesis: thioredoxin (TrxR, which is overexpressed in cancers as a defence against oxidative stress) and CA IX/XII, involved in metabolism and pH regulation in tumours ( Figure 18 ). Indeed, variously substituted sulphocoumarins acted as low nanomolar hCA IX/XII inhibitors and showed micromolar activity against TrxR, a selenium-containing enzyme ( Figure 18 ).…”

“…In a rhodaminebased test for evaluating multidrug resistance to antitumor agents in LoVo/DOX cells, that overexpress both P-gp and CA XII, some of the coumarin derivatives 41 were able to revert the phenomenon, leading to an increased uptake of doxorubicin within the tumour cell, demonstrating thus the efficacy of the hybridisation approach 73 . Recently, Krasavin et al 74,75 proposed another interesting multitargeting approach of two enzymes involved in cancerogenesis: thioredoxin (TrxR, which is overexpressed in cancers as a defence against oxidative stress) and CA IX/XII, involved in metabolism and pH regulation in tumours (Figure 18). Indeed, variously substituted sulphocoumarins acted as low nanomolar hCA IX/XII inhibitors and showed micromolar activity against TrxR, a seleniumcontaining enzyme (Figure 18).…”