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Abstract
Drug combination represents one of the most accredited strategies of cancer therapy able to improve drug efficacy and possibly overcome drug resistance. Among the agents used to complement conventional chemotherapy, carbonic anhydrase IX (CAIX) inhibitors appear as one of the most suitable, as markers of hypoxic and acidic cancer cells which do not respond to chemo- and radiotherapy. We performed preclinical in vitro assays to evaluate whether the SLC-0111 CAIX inhibitor co-operates and potentiates the cytotoxic effects of conventional chemotherapeutic drugs in A375-M6 melanoma cells, MCF7 breast cancer cells, and HCT116 colorectal cancer cells. Here, we demonstrate that the SLC-0111 CAIX inhibitor potentiates cytotoxicity of Dacarbazine and Temozolomide currently used for advanced melanoma treatment. SLC-0111 also increases breast cancer cell response to Doxorubicin and enhances 5-Fluorouracil cytostatic activity on colon cancer cells. These findings disclose the possibility to extend the use of CAIX inhibitors in the combination therapy of various cancer histotypes.
Highlights
Therapy resistance represents the main issue for cancer treatment and obstacles the good outcome of cancer patients
We demonstrated that SLC-0111, a novel carbonic anhydrase IX (CAIX) inhibitor, is able to synergise with Dacarbazine and its derivative Temozolomide, Doxorubicin and 5-Fluorouralcil in the treatment of melanoma, breast, and colorectal cancer, respectively, which, as reported in our previous paper[10], express a significant level of mRNA and protein of CAIX in normoxia
Ãp < 0.05, One-way ANOVA, N 1⁄4 3. (f) Chemical structure of SLC-0111. Both showing that the percentage of dead cells upon Temozolomide treatment is almost doubled when combined with SLC-0111. To further prove such data, we extended Temozolomide and SLC-0111 treatment to 14 days by performing a colony formation assay (Figure 1(e)) and observed similar results: in particular, while the number of developed colonies upon SLC-0111 treatment is comparable to control, the decrease obtained with Temozolomide treatment alone is further enhanced when used in combination with the CAIX inhibitor
Summary
Therapy resistance represents the main issue for cancer treatment and obstacles the good outcome of cancer patients. The issue of drug resistance regards the so-called personalised medicine, developed from the genetic information collected from tumour tissues, based on targeted anticancer drugs that often involves kinase inhibitors[2]. Despite the significant progresses in the development of anticancer therapeutic strategies, involving either conventional or targeted therapies, drug resistance still represents a common phenomenon in tumourbearing patients. Complementary therapy may reduce the incidence of resistance as increasing drug efficacy and the overall survival rate of treated patients. This is why a large part of the effort dedicated to cancer therapy is directed towards the study for drug combinations
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