Sulfocoumarins, specific carbonic anhydrase IX and XII inhibitors, interact with cancer multidrug resistant phenotype through pH regulation and reverse P-glycoprotein mediated resistance

Nordfors

et al. 2020

Cancers

Carbonic anhydrases (CAs) are zinc-containing metalloenzymes that participate in the regulation of pH homeostasis in addition to many other important physiological functions. Importantly, CAs have been associated with neoplastic processes and cancer. Brain tumors represent a heterogeneous group of diseases with a frequently dismal prognosis, and new treatment options are urgently needed. In this review article, we summarize the previously published literature about CAs in brain tumors, especially on CA II and hypoxia-inducible CA IX and CA XII. We review here their role in tumorigenesis and potential value in predicting prognosis of brain tumors, including astrocytomas, oligodendrogliomas, ependymomas, medulloblastomas, meningiomas, and craniopharyngiomas. We also introduce both already completed and ongoing studies focusing on CA inhibition as a potential anti-cancer strategy.

Section: Use Of Ca Inhibitors In Brain Tumorsmentioning

confidence: 99%

The Expression of Carbonic Anhydrases II, IX and XII in Brain Tumors

Nordfors

et al. 2020

Cancers

“…Among the molecules most expressed in hypoxic condition, the carbonic anhydrase IX (CAIX) is considered a marker of hypoxia in vivo (17), whose overexpression has been correlated with increased tumor aggression in different types of cancer (18)(19)(20)(21)(22). To date, a series of CAIX inhibitors have been synthesized, both in the form of small inhibitory molecules and as monoclonal antibodies, used as antitumor agents in different models of neoplasms (23)(24)(25)(26)(27)(28)(29)(30)(31). In a previous work we tested the expression of CAIX in several human solid tumors, extending the CAIX expression information to the expression of the stem cells markers CD44 and nestin in solid cancers, to explore their relationship with the biological behavior of tumors.…”

Section: Discussionmentioning

confidence: 99%

Tissue Expression of Carbonic Anhydrase IX Correlates to More Aggressive Phenotype of Basal Cell Carcinoma

et al. 2021

Basal cell carcinoma (BCC) is the most common cancer in the white-skinned population accounting for about 15% of all neoplasms. Its incidence is increasing worldwide, at a rate of about 10% per year. BCC, although infrequently metastasizing, very often causes extensive tissue losses, due to the high propensity toward stromal infiltration, particularly in its dedifferentiated forms, with disfiguring and debilitating results. To date, there still is limited availability of therapeutic treatments alternative to surgery. We evaluated the immunohistochemical expression of the carbonic anhydrase IX (CAIX), one of the main markers of tissue hypoxia, in a set of 85 archived FFPE BCC tissues, including the main subtypes, with different clinical outcomes, to demonstrate a possible relationship between hypoxic phenotype and biological aggressiveness of these neoplasms. Our results showed that the expression level of the CAIX protein contributes to the stratification of BCC in the different risk classes for recurrence. We hypothesize for CAIX a potential therapeutic role as a target therapy in the treatment of more aggressive BCCs, thus providing an alternative to surgical and pharmacological therapy with Hedgehog inhibitors, a promising example of target therapy in BCCs.

Journal of Enzyme Inhibition and Medicinal Chemistry

“…This fairly populated category of compounds possessing moderate to low inhibitory properties towards recombinant hCA IX/XII features many compounds that are based on privileged chemotypes (e.g. [20][21][22][23][24][25]. Evidently, in most studies, these relatively inactive molecules would have not been progressed based solely on their inhibitory profile.…”

Section: Discussionmentioning

confidence: 99%

“…Such inconsistencies occurring between the ability of some hCA inhibitors to block the recombinant enzyme catalytic function and their effects on cancer cells constitute a challenge that has been much less addressed, in comparison to those related to the SAR and selectivity studies [22][23][24] . Thus, although the potential of hCA IX and XII as anticancer targets is supported by much evidence, including the welldocumented efficacy of hCA-inhibitory antibodies in vitro and in vivo, the success rate of small-molecule inhibitors upon the transition to cell culture setting is still below the desirable level 18,[25][26][27][28][29] . Taking this into account, attempts to re-evaluate the conventional drug discovery workflow that has existed in this field are of importance.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory activity against carbonic anhydrase IX and XII as a candidate selection criterion in the development of new anticancer agents

Krasavin

Kalinin

Sharonova

et al. 2020

Analysis of the literature data reveals that while inhibition of cancer-related carbonic anhydrase IX and XII isoforms continues to be an important enrichment factor for designing anticancer agent development libraries, exclusive reliance on the in vitro inhibition of these two recombinant isozymes in nominating candidate compounds for evaluation of their effects on cancer cells may lead not only to identifying numerous compounds devoid of the desired cellular efficacy but also to overlooking many promising candidates which may not display the best potency in biochemical inhibition assay. However, SLC-0111, now in phase Ib/II clinical trials, was developed based on the excellent agreement between the in vitro, in vivo and more recently, in-patient data.