Carcinostatic effects of diverse ascorbate derivatives in comparison with aliphatic chain moiety structures: Promotion by combined hyperthermia and reduced cytotoxicity to normal cells

In this study, using human tongue squamous carcinoma cells (HSC-4) carcinostatic activity was compared for diverse L-ascorbic acid (Asc) derivatives, including the 'straight-C-16-chain types', 6-O-palmitoyl-Asc (A6-P) and Asc-2-phosphate-6-O-palmitate sodium salt (APPS), as well as the 'branched-C-16-chain types', Asc-2-phosphate-6-O-(2'-hexyl) decanoate (APHD), an isomer of APPS, and Asc-2,3,5,6-O-tetra-(2'-hexyl)decanoate (VCIP). The order of magnitude of the carcinostatic effects at 37 degrees C was: APPS>A6-P = APHD>VCIP and at 42 degrees C was APPS = A6-P>APHD>VCIP. Therefore, the two straight-C-16-chain derivatives, APPS and A6-P, had a greater effect compared to the two branched-C-16-chain Asc derivatives, which are considered to have more difficulty with 'orientation along cell-membrane-glycerolipid direction'. APPS-treated HCS-4 cells were observed for a decrease in cell number, cell shrinkage, pycnosis indicative of apoptosis and cell deformation. The order of cytotoxicity for the normal human dermal fibroblasts (OUMS-36) at 37 degrees C was: A6-P (50% inhibitory concentration: 150-300 mu M)>APHD (450-600 mu M)>>Asc = APPS (800-1000 mu M). Accordingly, APHD was more cytotoxic than APPS, since the straight-C-16-chain type, which was eliminated after the enzymatic esterolysis of APPS, is metabolized via the 'fatty acid alpha-oxidation cycle' more efficiently in normal cells. Thus, APPS had a greater advantage over APHD, A6-P and VCIP in terms of carcinostatic effects at 37 degrees C, carcinostasis promotion at 42 degrees C and a decrease of cytotoxicity to normal cells. This observation suggests a marked potential for aliphatic chain-moiety structures as anticancer agents, due to their cancer-selective carcinostasis and combined efficacy with hyperthermia, without causing side effects.