Abstract
Abstract Purpose: The 18-kDa translocator protein (TSPO) in mitochondria is proapoptotic and upregulated in several types of cancers, particularly in colorectal cancer (CRC). This study aimed to develop a mitochondria-targeted doxorubicin prodrug and to investigate its cytotoxicity in human CRC (TSPO positive) and HCC (TSPO negative) cell lines. Methods: Mitochondria-targeted Doxorubicin Prodrug was synthesized by conjugation of a functional TSPO ligand with doxorubicin via an enzyme-cleavable linkage. Fluorescence cell viability assays in HT29, HCT116, HepG2 and Hep3B cells incubated with 5, 10, 25 and 50μM of Prodrug vs. Doxorubicin alone were performed using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega, Madison, MI, USA) at 6, 12, 24, 48, 60 and 72 hrs. T-tests were used for all comparisons (significance <.05). Results: Significantly decreased cell viability in TSPO positive CRC cell lines (HCT116 and HT-29) with both the prodrug and doxorubicin vs. controls was observed (p<0.05). In HCT116, 10 and 25μM prodrug demonstrated significantly higher cytotoxicity vs. doxorubicin at 48 and 60 hrs, with plateau in effect at 72 hrs; 50μM prodrug had significantly higher cytotoxicity vs. doxorubicin alone at all time points (p<.05 for all). In HT-29, 25 and 50μM prodrug had significantly higher cytotoxicity vs. doxorubicin at 48 and 60 hrs (p<.05). In TSPO negative HCC cell lines (Hep3B and HepG2), prodrug and doxorubicin vs. control showed significantly decreased cell viability at all time points except for 10μM at 24 hrs; 25 and 50μM prodrug demonstrated similar cytotoxicity vs. doxorubicin at all time points except at 60 hours (p<.05 for all). Conclusion: Our novel mitochondria-targeted doxorubicin prodrug demonstrated superior cytotoxicity compared to doxorubicin in human CRC cell lines. Citation Format: Jemianne Jia, Minzhi Xing, Xiaoxi Ling, Mingfeng Bai, Hyun S. Kim. Novel mitochondria-targeted Doxorubicin Prodrug for colorectal cancer and hepatocellular carcinoma: In vitro studies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4407. doi:10.1158/1538-7445.AM2015-4407
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