Anti-tumor effects of a penetratin peptide targeting transcription of e2f-1, 2 and 3a is enhanced when used in combination with pemetrexed or cisplatin

Gulam Mohmad Rather, Michael Anyanwu, Tamara Minko, Olga Garbuzenko, Zoltan Szekely, Joseph Bertino

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background: We tested the antitumor effects of a modified E2F peptide substituting D-Arg for L-Arg, conjugated to penetratin (PEP) against solid tumor cell lines and the CCRF-leukemia cell line, alone and in combination with pemetrexed or with cisplatin. For in-vivo studies, the peptide was encapsulated in PEGylated liposomes (PL-PEP) to increase half-life and stability. Methods: Prostate cancer (DU145 and PC3), breast cancer (MCF7, MDA-MB-468, and 4T1), lymphoma (CCRF-CEM), and non-small cell lung cancer (NSCLC) cell lines (H2009, H441, H1975, and H2228) were treated with D-Arg PEP in combination with cisplatin or pemetrexed. Western blot analysis was performed on the NSCLC for E2F-1, pRb, thymidylate synthase, and thymidine kinase. The H2009 cell line was selected for an in-vivo study. Results: When the PEP was combined with cisplatin and tested against solid tumor cell lines and the CCRF-CEM leukemia cell line, there was a modest synergistic effect. A marked synergistic effect was seen when the combination of pemetrexed and the PEP was tested against the adenocarcinoma lung cancer cell lines. The addition of the PEP to pemetrexed enhanced the antitumor effects of pemetrexed in a xenograft of the H2009 in mice. Con-clusions: The D-Arg PEP in combination with cisplatin caused synergistic cell kill against prostate, breast, lung cancers, and the CCRF-CEM cell line. Marked synergy resulted when the D-Arg PEP was used in combination with pemetrexed against the lung adenocarcinoma cell lines. A xenograft study using the PL-PEP in combination with pemetrexed showed enhanced anti-tumor effects com-pared to each drug alone.

Original languageEnglish (US)
Article number972
Pages (from-to)1-15
Number of pages15
JournalCancers
Volume13
Issue number5
DOIs
StatePublished - Mar 1 2021

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Keywords

  • Cisplatin
  • E2F
  • NSCLC
  • Pemetrexed
  • Thymidine kinase
  • Thymidylate synthase

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