Abstract
Thymidine kinases (TKs) have been considered one of the potential targets for anticancer therapeutic because of their elevated expressions in cancer cells. However, nucleobase analogs targeting TKs have shown poor selective cytotoxicity in cancer cells despite effective antiviral activity. 3′-Deoxythymidine phenylquinoxaline conjugate (dT-QX) was designed as a novel nucleobase analog to target TKs in cancer cells and block cell replication via conjugated DNA intercalating quinoxaline moiety. In vitro cell screening showed that dT-QX selectively kills a variety of cancer cells including liver carcinoma, breast adenocarcinoma and brain glioma cells; whereas it had a low cytotoxicity in normal cells such as normal human liver cells. The anticancer activity of dT-QX was attributed to its selective inhibition of DNA synthesis resulting in extensive mitochondrial superoxide stress in cancer cells. We demonstrate that covalent linkage with 3′-deoxythymidine uniquely directed cytotoxic phenylquinoxaline moiety more toward cancer cells than normal cells. Preliminary mouse study with subcutaneous liver tumor model showed that dT-QX effectively inhibited the growth of tumors. dT-QX is the first molecule of its kind with highly amendable constituents that exhibits this selective cytotoxicity in cancer cells.
Highlights
With cancers being the leading cause of death world-wide, developing safe and effective anticancer agents remains in urgent need
Cytosolic thymidine kinases (TKs) are only present at a low level in the S phase of cells; whereas elevated level of TKs have been observed in virus infected cells and rapidly proliferating cancer cells [5,6,7,8], e.g., lung tumors and breast cancer tissues [9,10]
We report here a novel 39-deoxythymidine phenylquinoxaline conjugate that selectively kills a variety of cancer cells, but not normal hepatocytes
Summary
With cancers being the leading cause of death world-wide, developing safe and effective anticancer agents remains in urgent need. These results suggested that the selective killing of cancer cells over normal liver cells by dT-QX was due to the unique covalent conjugation of cytotoxic phenylquinoxaline moiety with 39-deoxythymidine. Doxorubicin was even more toxic toward normal liver 7702 cells than liver cancer Hep3B or H22 cells at concentrations above 0.5 mM (Figure 3e).
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