Salvestrols Target Cancer Death Receptors

Salvestrol Q40 has been found to induce cancer cell death by upregulation of death receptors leading to apoptosis. The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising target for cancer therapeutics. However, some tumor cells are resistant to TRAIL-induced apoptosis. Previous studies have shown that salvestrol Q40, a naturally occurring flavonoid, induces the up-regulation of death receptor 5 (DR5), which is a receptor for TRAIL. Here, we show for the first time that salvestrol Q40 synergistically acts with exogenous soluble recombinant human TRAIL to induce apoptosis in HeLa cervical cancer cells, but not in normal human peripheral blood mononuclear cells. The combined use of salvestrol Q40 and TRAIL induced Bid cleavage and the activation of caspase-8. Also, human recombinant DR5/Fc chimera protein, caspase inhibitors, and DR5 siRNA efficiently reduced apoptosis induced by co-treatment with salvestrol Q40 and TRAIL. These results raise the possibility that treatment with salvestrol Q40 might be promising as a new therapy against all types of cancer.
In studies against thyroid cancer cell lines, salvestrol T30 and salvestrol Q40 were the most effective inhibitors found. Salvestrol T30 was shown to inhibit cancer cell signal transduction and induce apoptosis. The scientists concluded that salvestrol T30 may provide a new approach for the treatment of human anaplastic thyroid carcinoma for which no effective therapy is presently available. Another study compared the effects of genistein, salvestrol T30, salvestrol Q40, chrysin and other flavonoids on human thyroid carcinoma cell lines. Among the flavonoids tested, salvestrol T30 and salvestrol Q40 were shown to be the most potent inhibitors of these cancer cell lines. The scientists noted that because these thyroid cancer cells lacked an anti-estrogen receptor binding site and an estrogen receptor, that salvestrol T30 and salvestrol Q40 are inhibiting these cancer cells via mechanisms involving CYP1B1 bioactivation. The scientists concluded that salvestrol T30 and salvestrol Q40 may represent a new class of therapeutic agents in the management of thyroid cancer.
To study the effects of various plant constituents, an examination was made of 21 different flavonoids on the growth of human breast cancer cells. Salvestrol T30 was shown to the most effective anti-proliferative flavonoid tested. A related study showed that flavonoids such as salvestrol T30 bind to estrogen receptor sites on cell membranes in order to prevent over-proliferation of these cells in response to estrogen.
A study assessed the antioxidant potencies of several dietary flavonoids compared with vitamin C. Pretreatment with all flavonoids and vitamin C produced dose-dependent reductions in oxidative DNA damage. When ranked in order of potency, only salvestrol T30, rutin and quercetin were more effective than vitamin C in reducing DNA oxidative damage.
Salvestrol T30 was tested to ascertain its effect on human leukemia cells. Salvestrol T30 was shown to induce apoptosis more effectively than quercetin and other flavonoids tested. The researchers attributed a unique mechanism of inducing apoptosis to the cancer preventive activity of salvestrol T30. Another study showed that salvestrol T30 and another flavonoid called salvestrol Q40 strongly inhibited the growth of human leukemia cells and induced these cells to differentiate. Topoisomerases are involved in many aspects of leukemic cell DNA metabolism such as replication and transcription reactions. In one study, quercetin or salvestrol T30 were shown to inhibit topoisomerase-catalyzed DNA irregularities. In a study of various agents used to induce differentiation of human promyelocytic leukemia cells, salvestrol T30 and salvestrol Q40 were among the flavonoids shown to cause these leukemia cells to mature into healthy monocytes and macrophages.