Synthetic compounds increase the effect of chemotherapeutics on colon cancer cells.
Due to the rapid cell division rate of tumors, the surrounding tissue is often insufficiently supplied with blood and therefore poorly provided with oxygen. This lack of oxygen contributes to solid tumors such as colon cancer responding less well to radiation or chemotherapy. Carbonic anhydrases, which catalyse the hydration and dehydration of carbon dioxide influence the tissue pH around tumors and are often increasingly produced in hypoxic tumors, which leads to acidification of the surrounding tissue and further increases the resistance of the tumor cells to therapy. The overexpression of carbonic anhydrases is therefore associated with a more aggressive tumor biology and a poorer prognosis. This makes carbonic anhydrases interesting targets for new drugs to support cancer therapy. In an international team, IPB and MLU chemists recently synthesized 20 new derivatives of 4-( pyrazolyl)benzenesulfonamide Ureas, which they named SH7a-t.
All SH7 compounds were tested for inhibition of the tumor-associated human carbonic anhydrases IX and XII and indeed showed inhibition of these enzymes in a low nanomolar range. Subsequently, the compounds were tested by the US National Cancer Institute for their activity on 60 different tumor cell lines. In this screening, a representative of this series, compound SH7s, proved to be the most promising candidate with a broad spectrum of activity against several cancer cell lines, including leukemia, lung cancer, melanoma as well as colon, prostate and breast cancer cell lines.
In further studies, the researchers found that SH7s greatly enhanced the effect of the clinically approved cancer drug Taxol® on colorectal cancer cell lines. However, this approximately 30-fold increase in Taxol efficacy by SH7s only occurred under hypoxic (oxygen-deficient) cell cultivation conditions. When the tumor cell cultures were supplied with sufficient oxygen, there was no increase in the effect of SH7s on the cancer drug. Taxol itself works only half as well under hypoxic conditions as under normoxic conditions. The scientists conclude that SH7s is a promising candidate for the chemosensitization of colorectal tumors and will probably also achieve good results in vivo. An effect of SH7s on other enzymes tested, especially kinases, as important signaling enzymes, could be ruled out by the scientists.
