LCA-AZT Conjugate Anti-Cancer invitro Activity

Abstract

Pseudo nucleoside or short pseudo aptamer and telomerase have been selected as novel ligands and receptors in our effort to discover new anti-cancer reagents. We proposed that lithocholic acid (LCA) could be able to play the role of a vehicle to transport major therapeutic moiety into cell membrane through oral administration, like cholic acid delivering fatty acids, peptides in gastrointestinal track, but it’s more hydrophobic. Zidovudine or azidothymidine (AZT) was used as targeting head or/and therapeutic reagent aiming reverse transcriptase that plays central role of cancer cell telomere repairing. Telomerase is a reverse transcriptase, the major TERT, or hTERT in humans is a catalytic subunit of the entire enzyme. Even though both LCA and AZT have anticancer activities respectively, the conjugate of LCA-AZT was designed as our initial pseudo short aptamer inhibitor of cancer telomerase to verify our hypothetic concept that pseudo short aptamers targeting cancer telomerase are able to shut down the cancer cell growth, and cause the cells eventually senescence and mortality. As a consequence, two lung cancer cell lines and two colorectal cancer cell lines were treated by the conjugate, except lung cancer cell H1299, the efficacy of the conjugate was better than the parent compounds apparently. It conformed and proofed also the docking predictions via the molecular computational simulation. The all cancer cells used by a CCK-8 assay appeared apoptosis in the range of 56 μM – 90 μM IC50 after exposure to the LCA-AZT conjugate. The effectiveness of the conjugate was also time dependent, because the telomerase is a kind of reverse transcriptase, the mechanism would be like the inhibition of reverse transcriptase in HIV virus, the inhibition of telomere repairing toward cell death would be time consumable.