Synthesis and Antiproliferative Activity of Hybrid Peptides for Ovarian and Prostate Cancer

Abstract

Ovarian carcinoma is the leading malignancy of the female congenital system with a high mortality rate. In ovarian carcinoma, inappropriate activation of BCL6 has been shown to predict poor prognosis and promote tumor progression whereas inhibition reduces proliferation of cancer. During the malignant transformation of ovarian surface epithelium cells, NRP1 expression was found to be threefold upregulated. We hypothesized that developing a hybrid peptide containing a BCL6 peptide inhibitor with an NRP1 peptide activator would enhance cytotoxic effects on the ovarian cancer cells. Therefore, we designed and synthesized a hybrid peptide conjugate (BNP) with a BCL6 binding motif (GLVATVKEAGRSIHEIPREEL) connected via two beta alanine residues as a linker to the NRP1 sequence (RPARPAR). Two control peptides were synthesized with nonfunctional motifs for BCL6 and NRP1 (B’NP and BN’P respectively). The antiproliferative activities of these hybrid peptides were evaluated using ovarian cancer (SKOV3), prostate cancer (PC3), and human embryonic kidney (HEK293) control cell lines. This study indicates that BN’P (peptide with a BCL6-inhibiting sequence without a NRP1-activating sequence) showed no significant inhibition on cell proliferation of HEK293 but a significant reduction of SKOV3 (73%) and PC3 (63%) at a concentration of 1 µM after 48 h of incubation. The PC3 cytotoxicity was found to be independent of BCL6 inhibition and was not likely resulted from BCL6 inhibition. BNP (peptide with a BCL6-inhibiting and NRP1-activating sequence) did not show any synergistic effect because of the nature of tissue penetration cannot be tested in-vitro. This leaves the value of this hybrid peptide for future in-vivo studies.