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 angiogenic cytokine expression (5).

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.

1. Liu T-Z, Hannafon B, Gill L, Kelly B, Benbrook DM. Flex-Hets differentially induce apoptosis in cancer over normal cells by directly targeting mitochondria. Mol Cancer Ther 2007;6:1814-22.

2. Masamha CP, Liu, T., Benbrook, D.M. SHetA2 targets cyclin D1 for proteasomal degradation through a GSK3β-independent mechanism leading to G1 cell cycle arrest. . AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2007 October 22-26; San Diego, CA, USA; 2007.

3. Liu T, Masamha CP, Chengedza S, Benbrook DM. Regulation of apoptosis, cell cycle progression and differentiation by SHetA2 in renal cancer cells is associated with alterations in Bcl-2, Cyclin D1 and E-Cadherin proteins. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2007 October 22-26; 2007.

4. Chengedza S, Liu T, Benbrook DM. SHetA2 Effects on Thymidine Phosphorylase and NF-kB activity. AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2007 October 22-26; San Diego, CA USA; 2007.

5. Myers, T., Chengedza, S., Lightfoot, S., Pan, Y., Dedmond, D., Cole, L., Tang, Y., Benbrook, D.M. (2008) Flexible Heteroarotinoid (Flex-Het) SHetA2 inhibits angiogenesis in vitro and in vivo. Investigational New Drugs, Published online: 18 September 2008. http://www.springerlink.com/content/aj864j6707w47513/fulltext.pdf