Targeted therapy for adrenocortical tumors in transgenic mice through their LH receptor by Hecate-human chorionic gonadotropin conjugate

Abstract

Novel strategies are needed for the treatment of adrenocortical tumors that are usually resistant to chemotherapy. Hecate, a 23-amino acid lytic peptide, was conjugated to the 15-amino acid (81-95) fragment of the human chorionic gonadotropin beta (CGbeta) chain, which would selectively kill cancer cells expressing the LH receptor (LHR) sparing the normal ones with LHR. To prove the principle that Hecate-CGbeta conjugate may eradicate tumors ectopically expressing plasma membrane receptors, transgenic (TG) inhibin alpha-subunit promoter (inhalpha)/Simian Virus 40 T-antigen mice, expressing LHR in their adrenal gland tumors, were used as the experimental model. Wild-type control littermates and TG mice with adrenal tumors were treated with either Hecate or Hecate-CGbeta conjugate at the age of 6.5 months for 3 weeks and killed 7 days after the last treatment. The Hecate-CGbeta conjugate reduced the adrenal tumor burden significantly in TG male but not in female mice, in comparison with Hecate-treated mice. Hecate-CGbeta conjugate treatment did not affect normal adrenocortical function as the serum corticosterone level between Hecate and Hecate-CGbeta conjugate groups were similar. The mRNA and protein expressions of GATA-4 and LHR colocalized only in tumor area, and a significant downregulation of gene expression was found after the Hecate-CGbeta conjugate in comparison with Hecate- and/or non-treated adrenal tumors by western blotting. This finding provides evidence for a selective destruction of the tumor cells by the Hecate-CGbeta conjugate. Hereby, our findings support the principle that Hecate-CGbeta conjugate is able to specifically destroy tumor cells that ectopically express LHR.