Flexible-Heteroarotinoids
(Flex-Hets)
To eliminate cancer cells without harming healthy
cells is the ultimate objective of cancer prevention. This objective appears to be met by a novel
class of synthetic compounds called Flexible Heteroarotinoids (Flex-Hets). In vivo
studies demonstrated that Flex-Hets induce differentiation and inhibit tumor
growth and angiogenesis without evidence of toxicity, skin irritation or
teratogenicity.
It appears that Flex-Hets directly target abnormalities found in
cancer mitochondria, without harming healthy mitochondria, because normal cells
derived from the same organ site as their corresponding cancer cell lines are
drastically less sensitive to Flex-Het effects on mitochondria and apoptosis. Furthermore, Bcl2 family mitochondrial
proteins are regulated in opposite directions in normal versus cancer cells by
the lead Flex-Het, SHetA2 (1).
Inhibition of cancer cell growth is accompanied by G1 cell cycle
arrest and degradation of Cyclin D1 (2, 3).
SHetA2 inhibits the activity of the NF-kB transcription factor through inhibition
of IKK phosphorylation and subsequent degradation of the NF- kB inhibitor IkBa (4).
The regulation of Bcl-2 proteins, TP, VEGF and tenasxin C by NF-kB, and the temporal effects of SHetA2 on
these proteins, suggest that NF-kB is one of the earliest proteins targeted
by SHetA2.
Anti-angiogenesis activity occurs through SHetA2 inhibition of
thymidine phosphorylase (TP, platelet derived endothelial cell growth factor
(PD-ECGF).
SHetA2 chemoprevention activity was
demonstrated in a 3-dimensional organotypic model of endometrial
carcinogenesis, in which the consistent DMBA (7,12-dimethylbenz[a]anthracene)
induction and SHetA2 prevention of the cancerous phenotype were validated by
karyometry. This carcinogenesis and chemoprevention was
validated in an independent laboratory.
Excreted proteins up-regulated by carcinogenesis and prevented by SHetA2
also were validated and may be useful biomarkers for cancer diagnosis.