N-carbamidoyl-4-((3-ethyl-2,4,4-trimethylcyclohexyl)methyl)benzamide enhances staurosporine cytotoxic effects likely inhibiting the protective action of Magmas toward cell apoptosis.
We recently demonstrated that Magmas overexpression protects GH-secreting rat pitutitary adenoma cell lines from apoptosis by inhibiting cytochrome c release from mitochondria after treatment with staurosporine, strongly suggesting a role of Magmas in preventing apoptosis. The aim of this study was to produce a drug that, by inhibiting Tim16, may sensitize chemoresistant tumor cell to proapoptotic stimuli. We synthesized six compounds and challenged their sensitizing effects toward the proapoptotic effects of staurosporine in the TT cell line, derived from a human medullary thyroid carcinoma. We found that compound 5, devoid of the planarity in the aliphatic part of the lead 1, is not cytotoxic but enhances the proapoptotic effects of staurosporine by reducing MMP activation. Compound 5 may be useful for cancer treatment in association with chemotherapeutic drugs, possibly allowing a reduction of the chemotherapeutic agent effective dose.
Section of Endocrinology, Department of Medical Sciences, University of Ferrara , 44121 Ferrara, Italy.
Maria Chiara
MC
Zatelli
Teresa
T
Gagliano
Michela
M
Pelà
Sara
S
Bianco
Valerio
V
Bertolasi
Federico
F
Tagliati
Remo
R
Guerrini
Ettore
E
degli Uberti
Severo
S
Salvadori
Claudio
C
Trapella
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors*; D019311:Staurosporine / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001549:Benzamides; D006146:Guanidines; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; C000590782:N-(4-(3-ethyl-2,4,4-trimethylcyclohexylmethyl)benzoyl)guanidine; C503439:PAM16 protein, human; D019311:Staurosporine