Chemical chaperone therapy for anaplastic thyroid carcinoma

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Patients with mutant p53 (mp53) tumors often display a worse prognosis than those with wild-type p53 (wtp53) tumors. The present study aimed to develop a novel strategy for overcoming this problem in mp53-targeting cancer therapy to restore the function of mutated proteins to that of wild-type proteins. We then examined restoration of CDDP-induced p53-dependent apoptosis by a chemical chaperone of glycerol against mp53 tumor cells. An anaplastic thyroid carcinoma cell line (8305c) carrying the mp53 gene was used. In culture, 8305c cells pretreated with glycerol became more sensitive to CDDP. Moreover, apoptotic bodies and DNA ladder formation were observed only in cells treated with glycerol and CDDP. Furthermore, the mechanisms of chemical chaperone therapy using DNA arrays and protein chips were investigated. When cells were pretreated with glycerol, mRNA expression for apoptosis-suppressive genes such as TRAF2,NIK,IKK,NFkB, and IAP was decreased. At the protein level, expression of these proteins was also decreased. These results suggest that not only p53 pathways but also NFkB pathways display deep relationships with chemical chaperone therapy using glycerol. Furthermore, in nude mice transplanted with tumors, clear delays in tumor growth were observed when tumors were treated with glycerol and CDDP. We thus expect chemical chaperone therapy to offer a new strategy for cancer therapy in mp53 tumors.