Repeated-dose toxicity of HSP27-binding heptapeptide in mice

Abstract

Heptapeptide, including seven amino acids of the PKC delta V5 region, which can bind HSP27 and abrogate HSP27-mediated resistance against IR and cisplatin ( Kim et al., 2007 ), was examined for single- and repeated-dose toxicity in mice. The single-dose experiment was performed with an intravenous and intraperitoneal injection of 100 mg/kg of heptapeptide, and the repeated-dose experiment was 14 doses over 28 days at 0, 5, 25, and 100 mg/kg of heptapeptide. Observations included clinical signs, mortality, body and organ weights, hematology, and serum biochemistry. No effects of heptapeptide on detected parameters were observed, and these findings indicated heptapeptide may be a possible therapeutic candidate without significant toxicity.

HspB1, HspB5 and HspB4 in Human Cancers: Potent Oncogenic Role of Some of Their Client Proteins

“…One example concerns the interaction of HspB1 with seven amino acids of the PKC delta-V5 heptapeptide region (residues 668 to 674, E-F-Q-F-L-D-I) of Protein Kinase C delta (PKCdelta). This PKC region can sensitize human cancer cells by sequestring HspB1, hence inhibiting its interaction with pathological protein partners [93,200]. This resulted in the inhibition of HspB1-mediated resistance against drugs, such as cisplatin and DNA damaging agents.…”

Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update

“…These approaches sensitized cancer cells to apoptotic inducers, anticancer drugs and radiations. Decreased tumorigenic and metastatic potentials of several cancer cells have been observed (Bausero et al 2006; Kamada et al 2007; Kaur et al 2011; Kim et al 2007; Lee and Lee 2010; Rocchi et al 2006; Straume et al 2012)(Gibert et al, 2012). RNAi targeting is believed to destabilize HspB1 interactome leading to the inactivation, destabilization and/or degradation of inappropriate, tumorigenic and/or metastatic client proteins.…”

“…The targets can be the oligomeric status or crucial modifications, such as the argpyrimidine modification which modulates HspB1 ability to bind cytochrome c (Padival et al 2003). The peptide sequence that characterizes the binding domain of a client protein is another possible way to tackle the problem, one example is the seven amino acids of the PKC delta V5 region which inhibit HspB1-induced resistance against DNA damaging agents and cisplatin (Kim et al 2007; Lee and Lee 2010). Testing existing drugs can sometime be successful, as for example the anti-viral drug RP101 (Bromovinyldeoxyuridine, Brivudine) which has recently been reported to improve the efficiency of human pancreatic cancer chemotherapy through a specific interaction with HspB1 (Heinrich et al 2011).…”

Heat Shock Protein 27-Targeted Heptapeptide of the PKCΔ Catalytic V5 Region Sensitizes Tumors With Radio- and Chemoresistance

“…When we examined the sensitizing effects of HEPT with IR or Cis in normal cell types such as human vascular endothelial cells (HUVEC), no synergistic sensitization by HEPT was observed, even though HUVEC showed high HSP27 protein expression (data not shown), suggesting cancerspecific selectivity by HEPT in radio-or chemosensitization. The 50% lethal dose of HEPT for mice by iv injection was more than 100 mg/kg (16), suggesting a lack of toxicity.…”

“…A heptapeptide (HEPT) that contains binding sequences of the PKCd catalytic V5 (PKCd-V5) region (FEQFLDI) inhibited the interaction of HSP27 with other apoptotic molecules such as cytochrome c and PKCd and restored PKCd activity that blocked HSP27-mediated radio-or chemoresistance in human lung and breast cancer cells (15). Fourteen treatments with HEPT (100 mg/kg of body weight given intravenously) in mice did not induce toxicity during a 2-month examination (16). However, detailed in vivo studies of tumor targeting or therapeutic effects of the abolition of radio-and chemoresistance were not performed.…”