Modulation of small G protein isoprenylation by anticancer monoterpenes in in situ mammary gland epithelial cells

Abstract

Monoterpenes have been shown to both prevent and treat mammary cancer in animal models and are currently in clinical testing in advanced cancer patients. In this study, we investigated a biochemical modulation associated with the antitumor activity of monoterpenes, the inhibition of protein isoprenylation in monoterpene chemoprevention target tissue, i.e. the in situ mammary gland epithelial cells. We first developed a new methodology that for the first time permitted the study of protein isoprenylation and other products in the mevalonate pathway in in situ mammary cells. Using this approach, we found that chronically feeding rats with an anticancer dose of perillyl alcohol resulted in a 22% inhibition of coenzyme Q synthesis and a 19% inhibition of small G protein isoprenylation in mammary gland epithelial cells in situ. The greatest inhibition of small G protein isoprenylation observed was the 28% inhibition of isoprenylation of RhoA by type I geranylgeranyl protein transferase (GGPTase). Given that some substrates of type I GGPTase, such as RhoA and Rac1, have transforming properties, the possibility that the inhibition of type I GGPTase will change the cellular location and functionality of these proteins and thus contribute to the chemoprevention activity of monoterpenes, is discussed.

Composition and cytotoxic activity of essential oils from Xylopia aethiopica (Dunal) A. Rich, Xylopia parviflora (A. Rich) Benth.) and Monodora myristica (Gaertn) growing in Chad and Cameroon

“…Adaramoye et al [24] also showed the antiproliferative effect of X. aethiopica extract on human cervical cancer cells. On the other hand, it was reported that components such as terpinen-4-ol and α-cadinol which are found in all the tested essential oils presented activity against breast, colon, gastric, lung, ovarian and laryngeal cancer cell lines [25]. In addition, β-pinene which is one of the most naturally occurring monoterpene found in the oil of Xylopia species, has shown a significant cytotoxic activity against breast cancer and epidermal skin cancer cell lines [26].…”

Glucocorticoid Down-regulation of RhoA Is Required for the Steroid-induced Organization of the Junctional Complex and Tight Junction Formation in Rat Mammary Epithelial Tumor Cells

“…In a complementary manner, ectopic expression of dominant negative RhoA (RhoA.N19) stimulates junctional remodeling in the absence of steroids. trials as breast cancer therapy, have been shown to inhibit the isoprenylation of RhoA and likely RhoA functionality (78). The Con8 cells used in our study are a tumorigenic mammary epithelial cell line (79), suggesting that utilization of RhoA is distinct from nontumorigenic cells such as the MDCK cell lines.…”

Pharmaceutical and therapeutic Potentials of essential oils and their individual volatile constituents: a review

“…POH either alone or with PA (perillic acid, the major metabolite of POH in the body), has a potential use as an anticancer drug that stimulates different types of tumors to apoptosis, inhibits their proliferation, or overcomes their resistance to chemo-/radiotherapy (Yuri et al, 2004;Samaila et al, 2004;Elegbede et al, 2003;Clark et al, 2003;Ahn et al, 2003;Bardon et al, 2002;Burke et al, 2002;Bardon et al, 1998). The antitumor activity of POH emanates from its activity of modulating cellular processes that control cell growth and differentiation (Azzoli et al, 2003;Clark et al, 2002;Ariazi et al, 1999;Ren and Gould, 1998;Gould, 1997 andGould, 1995). Thus POH, among other micronutrients, was investigated by the National Cancer Institute (NCI) in NCI-sponsored phase I, II, or III chemoprevention trials for prostate, breast and colon cancers (Greenwald et al, 2002).…”