A conjugate of the lytic peptide Hecate and gallic acid: structure, activity against cervical cancer, and toxicity.

Conjugate compounds constitute a new class of molecules of important biological interest mainly for the treatment of diseases such as cancer. The N-terminus region of cationic peptides has been described as important for their biological activity. The aim of this study was to evaluate the lytic peptide Hecate (FALALKALKKALKKLKKALKKAL) and the effect of conjugating this macromolecule with gallic acid (C7H6O5) in terms of structure, anti-cancer activity, and toxicity. An N-terminus GA-Hecate peptide conjugate was synthesized to provide information regarding the relationship between the amino-terminal region and its charge and the secondary structure and biological activity of the peptide; and the effects of gallic acid on these parameters. Peptide secondary structure was confirmed using circular dichroism (CD). The CD measurements showed that the peptide has a high incidence of α-helical structures in the presence of SDS and LPC, while GA-Hecate presented lower incidence of α-helical structures in the same chemical environment. An evaluation of the anti-cancer activity in HeLa cancer cells indicated that both peptides are active, but that coupling gallic acid at the N-terminus decreased the activity of the free peptide. GA-Hecate showed lower activity in non-tumor keratinocyte cells but higher hemolytic activity. Our findings suggest that the N-terminus of Hecate plays an important role in its activity against cervical cancer by affecting it secondary structure, toxicity, and hemolytic activity. This study highlights the importance of the N-terminus in antitumor activity and could provide an important tool for developing new anti-cancer drugs.

Differential effects of raloxifene, tamoxifen and fulvestrant on a murine mammary carcinoma.

The purpose of this study was to evaluate the effect of the selective estrogen receptor modulators raloxifene and tamoxifen and of the pure antiestrogen fulvestrant on tumor growth and progesterone receptor (PR) expression in an experimental model of breast cancer. The effects of these compounds on cell proliferation were studied in primary cultures of a progestin-dependent mammary carcinoma tumor line, in the presence of medroxyprogesterone acetate (MPA) or 17-beta-estradiol (E2). In in vivo studies the tumor was inoculated subcutaneously in BALB/c female mice treated with 20 mg MPA depot. Raloxifene (12.5 mg/kg) or tamoxifen (5 mg/kg) were administered in daily doses or E2 silastic pellets (5 mg) were implanted. When the tumors reached about 25-50 mm2 MPA was removed in half of the animals. E2 induced complete tumor regressions, tamoxifen inhibited tumor growth in vivo while raloxifene disclosed proliferative effects in animals in which MPA had been removed. In vitro, E2 inhibited cell proliferation at concentrations higher than 10(-14)M. Raloxifene and fulvestrant, but not tamoxifen, partially reverted E2-induced inhibition. Fulvestrant and tamoxifen inhibited MPA-induced cell proliferation while raloxifene had a stimulatory effect. Tamoxifen and E2 increased, raloxifene induced no effect, and fulvestrant significantly decreased PR expression. In this study we provide evidence for differential effects of tamoxifen and raloxifene on experimental mammary tumors. Since raloxifene is under evaluation for use in breast cancer prevention, these results may have important clinical implications.