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Ji Won Kim

Ji Won Kim

Inha University, South Korea

Title: Induced Phenotype Targeted Chemotherapy with Checkpoint Kinase 1 Inhibitor

Biography

Biography: Ji Won Kim

Abstract

Backgound: We suggested a novel strategy termed induced phenotype targeted therapy (IPTT) using radiation. The aim of this study is to expand the the clinical implications of IPTT including metastatic tumors. We investigated the candidate drugs such as checkpoint kinase 1 (Chk 1) inhibitor to induce phenotype caspase-3 and found the mechanism of activating the prodrug.

Methodology & Theoretical Orientation: We designed a caspase-3 specific activatable prodrug, DEVD-S-DOX, containing doxorubicin linked to a peptide moiety (DEVD) cleavable by caspase-3 upon apoptosis. To induce apoptosis systemically in the metastatic tumor, we used a Chk 1 inhibitor, LY2603618. clonogenicity, cell cycle distribution and apoptosis were assessed in breast cancer cell lines with prodrug and LY2603618, seperatively, and combination.The in vivo antitumor activity of the caspase-3-specific activatable prodrug combined with LY2603618 was investigated in C3H/HeN tumor-bearing mice (n = 5 per group) and analyzed with the Student's t test or Mann-Whitney U test. All statistical tests were two-sided. We confirmed the basic principle using a caspase-sensitive nanoprobe (Apo-NP).

Findings: The in vitro studies showed that the cell cycle arrest of p53-deficient cancer cells by Chk1 inhibitor, thus leading to facilitated caspase-3 upon apoptosis. The growth of MDA-MB-231, which is p53-deficient, was effectively suppressed by daily oral administration of LY2603618 when treated with DEVD-S-DOX in vivo without evident toxicities.

Conclusion & Significance: The combination therapy using DEVD-S-DOX and Chk1 inhibitor could effectively treat p53-deficient breast cancer by selectively chemosensitizing cancer cells with low toxic adverse effects.

References:

  1. Lee BS, Cho YW, Kim GC, Lee DH, Kim CJ, Kil HS, Chi DY, Byun Y, Yuk SH, Kim K, Kim IS, Kwon IC, Kim SY. Induced phenotype targeted therapy: radiation-induced apoptosis-targeted chemotherapy. J Natl Cancer Inst. 2014 Dec 12;107(2).
  2. Chung SW, Choi JU, Lee BS, Byun J, Jeon OC, Kim SW, Kim IS, Kim SY, Byun Y. Albumin-binding caspase-cleavable prodrug that is selectively activated in radiation exposed local tumor. Biomaterials. 2016 Jul;94:1-8.
  3. Chung SW, Kim GC, Kweon S, Lee H, Chang HW, Kim JW, Son WC, Kim SY, Byun Y. Metronomic oral doxorubicin with combination of Chk1 inhibitor for the treatment of p53-deficient breast cancer. Mol Cancer Ther.submitted