Carbonic Anhydrase IX Inhibitors as Candidates for Combination Therapy of Solid Tumors

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.

Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies

“…Various combinations of CA-inhibitors have been described in the literature. The majority of them exhibited synergic activity in cancer cells as described in 204 . Moreover, antibodies targeting CAIX and CAXII have been developed.…”

“…Thus combination therapies involving various anticancer agents have been shown to exhibit profound antitumor efficiency when used with CAIX/CAXII inhibitors 90 , 111 , 159–161 . This topic has been recently reviewed in 204 .…”

Suppression of Tumor Growth and Cell Migration by Indole-Based Benzenesulfonamides and Their Synergistic Effects in Combination with Doxorubicin

“…However, CA IX is also implicated in the development of drug resistance [ 6 , 35 ]. In order to avoid the possible drug resistance and/or to improve its cytotoxic efficacy, attempts have been made to study the effects of CA IX inhibitors in combination with conventional chemotherapy [ 42 , 43 , 44 ]. For instance, in vitro preclinical studies demonstrated that SLC-0111 complemented and potentiated the cytotoxic effects of conventional chemotherapeutic drugs, including dacarbazine and temozolomide in A375-M6 melanoma cells, DOX in MCF-7 breast cancer cells, and 5-fluorouracil in HCT116 colorectal cancer cells [ 19 ].…”

Cancer Therapeutic Targeting of Hypoxia Induced Carbonic Anhydrase IX: From Bench to Bedside

“…This has been borne out in a number of in vitro and in vivo tumor models. Combining CAIX inhibitors with standard of care chemotherapy agents has been demonstrated to be significantly more efficacious than single agents alone [ 38 , 39 , 40 ]. Thus, combining the CAIX inhibitor, SLC-0111 with paclitaxel or with sunitinib in breast cancer [ 19 , 41 ], with temozolomide in pediatric and adult glioblastoma [ 42 ], with gemicitabine in pancreatic cancer [ 43 ], or an analog of SLC-0111, FC531, with cytarabine or Quizartinib in acute myeloblastic leukemia (AML) [ 44 ], results in greater inhibition of tumor growth and in significant increases in the survival of the tumor bearing mice.…”