Clotrimazole decreases glycolysis and the viability of lung carcinoma and colon adenocarcinoma cells

Tumor apoptosis induced by ruthenium(II)‐ketoconazole is enhanced in nonsusceptible carcinoma by monoclonal antibody to EGF receptor

“…Another azole derivative which shows potentially useful antitumor activity is CTZ, recognized as a calmodulin antagonist and inhibitor of glycolysis and known to be the primary energy source in most cancer cells. 8 CTZ induced significant reduction in glycolysis and ATP levels, which led to tumor cell destruction after 3 hr. 8 There is a need to enhance the efficacy of potentially useful anticancer agents like KTZ and CTZ and to develop new compounds capable of activity against tumor cells refractory to apoptosis since the latter property usually correlates with drug resistance.…”

“…8 CTZ induced significant reduction in glycolysis and ATP levels, which led to tumor cell destruction after 3 hr. 8 There is a need to enhance the efficacy of potentially useful anticancer agents like KTZ and CTZ and to develop new compounds capable of activity against tumor cells refractory to apoptosis since the latter property usually correlates with drug resistance.Since genetic alterations involving p53 mutation frequently correlate with decreased response to cancer chemotherapy, 9,10 we investigated whether Ru(II) complexes with CTZ or KTZ 11-13 are more effective than the parent compounds at promoting cell death in tumors with such genetic changes. The reason for this study with Ru(II)-azole complexes is to expand the range of potentially useful antitumor Ru agents since an Ru(III) complex like NAMI-A, 14 -16 which may require reduction of its Ru(III) moiety to act, has shown promising anticancer activity in initial clinical trials.…”

“…The mitochondrial damage induced by NAMI-A 16 is compatible with the effect of 20 -50 M CTZ, which induces glycolysis-related hexokinase detachment from mitochondria and loss of viability in B16 melanoma. 8 Since apoptosis induced by 50 M KTZ is decreased in colorectal and hepatocellular carcinoma cell lines with a defective p53-dependent pathway, 7 which also hampers the efficacy of cisplatin, 9,10 we investigated whether KTZ-Ru(II) complexes 11-13 are more active than KTZ or Ru(II) alone against tumor cells harboring p53 mutation. 19,20 We also investigated some of the mecha-…”

“…8 CTZ induced significant reduction in glycolysis and ATP levels, which led to tumor cell destruction after 3 hr. 8 There is a need to enhance the efficacy of potentially useful anticancer agents like KTZ and CTZ and to develop new compounds capable of activity against tumor cells refractory to apoptosis since the latter property usually correlates with drug resistance.…”

“…The mitochondrial damage induced by NAMI-A 16 is compatible with the effect of 20 -50 M CTZ, which induces glycolysis-related hexokinase detachment from mitochondria and loss of viability in B16 melanoma. 8 Since apoptosis induced by 50 M KTZ is decreased in colorectal and hepatocellular carcinoma cell lines with a defective p53-dependent pathway, 7 which also hampers the efficacy of cisplatin, 9,10 we investigated whether KTZ-Ru(II) complexes [11][12][13] are more active than KTZ or Ru(II) alone against tumor cells harboring p53 mutation. 19,20 We also investigated some of the mechaAbbreviations: CTZ, clotrimazole, 1-[(2-chlorophenyl)diphenylmethyl]-1H-imidazole; EGF-R, epidermal growth factor receptor; IC 50 , concentration that inhibits 50%; KTZ, ketoconazole, cis 4 , dichlorotetrakis(acetonitrile) Ru(II); wt, wild type; [X( 6 -arene)(en)Ru(II)], X ϭ Cl, MeCN, arene ϭ benzene, p-cymene, en ϭ 1,2-ethylenediamine; cisplatin, cis-diamminedichloroplatinum(II).…”