Cytotoxic Activity of Abietane-Type Diterpenes Isolated From Taxodium distichum Against Cancer Cells Adapted to Nutrient-Starved Conditions

Abstract

The mechanisms of cancer cell adaptation to tumor microenvironmental conditions, such as hypoxia and nutrient starvation, are currently receiving much attention as possible therapeutic targets. In an attempt to identify selectively cytotoxic substances against cancer cells adapted to nutrient starvation, 4 abietane-type diterpenes, sugiol (1), 6-α-hydroxysugiol (2), cryptojaponol (3), and 6-hydroxy-5,6-dehydrosugiol (4), were isolated from the bark of Taxodium distichum L. Rich var. distichum (bald cypress). Compounds 1, 2, and 4 showed potent cytotoxic activity against PANC-1 cells adapted to nutrient-starved conditions with half-maximal effective concentration (EC50) values of 6.4-9.2 µM, whereas the EC50 values of these compounds against PANC-1 cells under general culture conditions were more than 100 µM. Alternatively, compound 3, which we report for the first time in the genus Taxodium, showed moderate cytotoxicity against PANC-1 cells under nutrient-starved conditions with an EC50 of 37.9 µM. The selective index (S.I.), which compared the activity under nutrient-starved conditions with that under general culture conditions, was low (7.9). Further investigation revealed that the selective cytotoxic activity of compound 2 might be affecting the mitochondria.