Sensitization of cancer cells to DNA damaging agents by imidazolines.
Apoptosis, or programmed cell death, is a cellular mechanism used to regulate cell number and eliminate damaged or mutated cells. Concomitant with the initiation of the apoptotic cell signal, chemotherapeutic agents also induce anti-apoptotic factors, such as NF-kappaB, which compromise the overall efficacy of chemotherapeutic anticancer treatment. Here we describe an adjuvant therapy in which a small molecule is used to sensitize cancer cells toward apoptosis induced by chemotherapeutics. Our results indicate that the imidazoline 1d modulates the pro-survival NF-kappaB pathway and selectively sensitizes cancer cells toward DNA damaging agents, thus enhancing the overall efficacy of the treatment. Pretreatment of cancer cells with the noncytotoxic imidazoline 1d (10 nM) resulted in a significant increase in apoptosis and anticancer efficacy of the clinically significant DNA damaging agents camptothecin and cisplatin. Noncancerous cells remained unaffected during this regimen.
Sharma
Vasudha
V
Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, USA.
Peddibhotla
Satyamaheshwar
S
Tepe
Jetze J
JJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048288:Imidazolines / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000473:pathology*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D048288:Imidazolines; D002945:Cisplatin; D002166:Camptothecin