Abstract
Combination therapy is becoming imperative for the treatment of many cancers, as it provides a higher chance of avoiding drug resistance and tumor recurrence. Among the resistance-conferring factors, the tumor microenvironment plays a major role, and therefore, represents a viable target for adjuvant therapeutic agents. Thus, hypoxia and extracellular acidosis are known to select for the most aggressive and resilient phenotypes and build poorly responsive regions of the tumor mass. Carbonic anhydrase (CA, EC 4.2.1.1) IX isoform is a surficial zinc metalloenzyme that is proven to play a central role in regulating intra and extracellular pH, as well as modulating invasion and metastasis processes. With its strong association and distribution in various tumor tissues and well-known druggability, this protein holds great promise as a target to pharmacologically interfere with the tumor microenvironment by using drug combination regimens. In the present review, we summarized recent publications revealing the potential of CA IX inhibitors to intensify cancer chemotherapy and overcome drug resistance in preclinical settings.
Highlights
Prevalent cancer treatment failure largely stems from anticancer drug resistance in tumors and represents one of the major challenges to the healthcare system in the XXI century
There is an urgent need for innovations overcoming the main causes of drug resistance, which include drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, epithelial-mesenchymal transition, and inherent tumor cell heterogeneity [2]
While drug target alteration and tumor cell heterogeneity are still extremely challenging to combat, microenvironment-based tumor protective mechanisms appear more tractable in terms of pharmacological targeting [3]
Summary
Prevalent cancer treatment failure largely stems from anticancer drug resistance in tumors and represents one of the major challenges to the healthcare system in the XXI century. One of the pioneering attempts to employ small molecular CA IX blockers to overcome cytostatic resistance in hypoxic (acidic) regions was made in 2012 by Geiling and colleagues who investigated the combined effect of CA pan-inhibitor acetazolamide (AZ) and doxorubicin (DOX) [33] To this end, the authors used colon carcinoma HT-29 (CA IX rich) and HCT 116 (CA IX poor) cell lines, as well as MDA-MB-435 human melanoma cells, stably transfected to express empty vector. Employ small molecular CA IX blockers to overcome cytostatic resistance in h (acidic) regions was made in 2012 by Geiling and colleagues who investigat combined effect of CA pan-inhibitor acetazolamide (AZ) and doxorubicin (DOX) [ This end, the authors used colon carcinoma HT-29 (CA IX rich) and HCT 116 (CA IX cell lines, as well as MDA-MB-435 human melanoma cells, stably tran4soffe3c1ted to e empty vector (EV1) or CA IX (CA9/18) (Figure 1). The a coibnyncrcAelaZusdetrdeedathtmtehteoanxttitcihnityethoeefffcDeeOlcltsXowifnitAChAZloIwtXre-CraiActhmIcXeelnelxst.piCrseolsnasvirogenres.leTylyh,reDealOauXttheedofrfistcocaoctynhcewlubadsloeudcnktahiffnaetgcttheodef CA IX, isefifnecsttorfuAmZetnretaatlmfeonrt icsalanrcgeelry creellaltsedtotomthaeibnlotackiningacoifdCiAc IpXH, we,hitchhuiss inhsatrmumpeenritnalgfotrhe mem trcaancseprocretllos ftowmeaaiknltayinbacsiidcicdpruHge,st,hiunsclhuadmipnegriDngOthXe. mThemisbpraonienttrwanaspsofrutrotfhwereaskulypported fabcatsicthdarutgtsh, iencwluedainkglyDOaXc.idTihcis dporuingt wmasefluprhthaelrasnupepxoerrteteddbyrtehdeufaccetdthatot txhieciwtyeakulnyder the coaIXcni-ddriicicthdiocreunlglslmaingeelaspi(hnFasilgtauntrheeex1e)Cr[t3Ae3d]I.rXed-uriccehd tcoexlilciltiynuensd(eFrigthuerseam1)e[c3o3n]d.itions against the CA
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