melitten and Body-Weight

A conjugate of a lytic peptide, hecate, and a 15-amino acid segment of the beta-chain of chorionic gonadotropin (CG) destroyed human prostate xenografts in nude mice by targeting LH receptors. Since these xenografts also express LHRH receptors, we prepared a LHRH-hecate conjugate and tested its ability to destroy PC-3 cells in vitro and in vivo.. LHRH-hecate was added to cultures of PC-3, BRF 41 T, DU145, and LNCaP cells in the presence and absence of steroids. PC-3 xenografts were established in nude male mice, which were treated with LHRH-hecate.. Injections of LHRH-hecate resulted in tumor growth arrest and marked reduction of tumor burden (62.2 mg/g body weight in saline controls vs. 10.5 mg/g body weight in treated mice; P < 0.0001); unconjugated LHRH and hecate had no effect on tumor burden and tumor viability (48.5 mg/g body weight in LHRH treated animals vs. 63.2 mg/g body weight in hecate treated mice). Marked tumor necrosis occurred in conjugate treated mice. Removal of steroids from the culture media decreased the sensitivity of LNCaP and PC-3 cells to the LHRH-hecate; adding estrogen restored the sensitivity.. LHRH-hecate may be effective in treating hormone dependent and independent prostate cancers.

Topics: Animals; Body Weight; Cell Death; Culture Media; Gonadotropin-Releasing Hormone; Humans; Male; Melitten; Mice; Mice, Nude; Necrosis; Neoplasms, Experimental; Peptides; Prostatic Neoplasms; Receptors, LHRH; Steroids; Transplantation, Heterologous; Tumor Cells, Cultured

Insulin resistance is followed by an islet adaptation resulting in a compensating increase in insulin secretion and hyperinsulinemia. The mechanism underlying this increased insulin secretion is not established. We studied whether islet phospholipase A(2) (PLA(2)) contributes by using C57BL/6J mice fed a high-fat diet, since we previously showed that the insulin responses to the two PLA(2)-activating insulin secretagogues carbachol and cholecystokinin (CCK) are enhanced in this model. CCK (100 nM) and carbachol (100 microM) stimulated [(3)H]AA efflux, reflecting PLA(2) activation, both in islets from mice after 12 weeks on high-fat diet and in controls. The efflux increase was more pronounced in islets from high-fat diet-fed mice during both CCK (by 93 +/- 46%; P = 0. 034) and carbachol (by 64 +/- 22%; P = 0.009) stimulation. Also a direct PLA(2) activation by mellitin (2 microg/ml) elicited a potentiated efflux in islets from the insulin-resistant mice (by 361 +/- 107%; P = 0.002). The results suggest that exaggerated non-glucose-induced PLA(2) activation contributes to the islet compensation in insulin resistance.

Topics: Animals; Arachidonic Acid; Blood Glucose; Body Weight; Carbachol; Diabetes Mellitus, Type 2; Dietary Fats; Enzyme Activation; Fatty Acids, Nonesterified; Female; Glucose; Hyperinsulinism; Insulin; Insulin Resistance; Insulin Secretion; Islets of Langerhans; Melitten; Mice; Mice, Inbred C57BL; Phospholipases A; Sincalide; Time Factors