The mevalonate pathway provides sterols for membrane structure and nonsterol intermediates for the post-translational modification and membrane anchorage of growth-related proteins, including the Ras, Rac, and Rho GTPase family. Mevalonate-derived products are also essential for the Hedgehog pathway, steroid hormone signaling, and the nuclear localization of Yes-associated protein and transcriptional co-activator with PDZ-binding motif, all of which playing roles in tumorigenesis and cancer stem cell function. The phosphatidylinositol-4,5-bisphosphate 3-kinase-AKT-mammalian target of rapamycin complex 1 pathway, p53 with gain-of-function mutation, and oncoprotein MYC upregulate the mevalonate pathway, whereas adenosine monophosphate-activated protein kinase and tumor suppressor protein RB are the downregulators. The rate-limiting enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), is under a multivalent regulation. Sterol regulatory element binding protein 2 mediates the sterol-controlled transcriptional downregulation of HMGCR. UbiA prenyltransferase domain-containing protein-1 regulates the ubiquitination and proteasome-mediated degradation of HMGCR, which is accelerated by 24, 25-dihydrolanosterol and the diterpene geranylgeraniol. Statins, competitive inhibitors of HMGCR, deplete cells of mevalonate-derived intermediates and consequently inhibit cell proliferation and induce apoptosis. Clinical application of statins is marred by dose-limiting toxicities and mixed outcomes on cancer risk, survival and mortality, partially resulting from the statin-mediated compensatory upregulation of HMGCR and indiscriminate inhibition of HMGCR in normal and tumor cells. Tumor HMGCR is resistant to the sterol-mediated transcriptional control; consequently, HMGCR is upregulated in cancers derived from adrenal gland, blood and lymph, brain, breast, colon, connective tissue, embryo, esophagus, liver, lung, ovary, pancreas, prostate, skin, and stomach. Nevertheless, tumor HMGCR remains sensitive to isoprenoid-mediated degradation. Isoprenoids including monoterpenes (carvacrol, L-carvone, geraniol, perillyl alcohol), sesquiterpenes (cacalol, farnesol, β-ionone), diterpene (geranylgeranyl acetone), “mixed” isoprenoids (tocotrienols), and their derivatives suppress the growth of tumor cells with little impact on non-malignant cells. In cancer cells derived from breast, colon, liver, mesothelium, prostate, pancreas, and skin, statins and isoprenoids, including tocotrienols, geraniol, limonene, β-ionone and perillyl alcohol, synergistically suppress cell proliferation and associated signaling pathways. A blend of dietary lovastatin and δ-tocotrienol, each at no-effect doses, suppress the growth of implanted murine B16 melanomas in C57BL6 mice. Isoprenoids have potential as adjuvant agents to reduce the toxicities of statins in cancer prevention or therapy.

In day-to-day life, we often must choose between pursuing familiar behaviors or adjusting behaviors when new strategies might be more fruitful. The dorsomedial striatum (DMS) is indispensable for arbitrating between old and new action strategies. To uncover molecular mechanisms, we trained mice to generate nose poke responses for food, then uncoupled the predictive relationship between one action and its outcome. We then bred the mice that failed to rapidly modify responding. This breeding created offspring with the same tendencies, failing to inhibit behaviors that were not reinforced. These mice had less post-synaptic density protein 95 in the DMS. Also, densities of the melanocortin-4 receptor (MC4R), a high-affinity receptor for α-melanocyte-stimulating hormone, predicted individuals’ response strategies. Specifically, high MC4R levels were associated with poor response inhibition. We next found that reducing Mc4r in the DMS in otherwise typical mice expedited response inhibition, allowing mice to modify behavior when rewards were unavailable or lost value. This process required inputs from the orbitofrontal cortex, a brain region canonically associated with response strategy switching. Thus, MC4R in the DMS appears to propel reward-seeking behavior, even when it is not fruitful, while moderating MC4R presence increases the capacity of mice to inhibit such behaviors.

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Objectives Xanthorrhizol, a sesquiterpene, and d-δ-tocotrienol, a vitamin E molecule, each suppresses the proliferation of a number of tumor cells. This study aims to examine the potentially synergistic effect of xanthorrhizol and d-δ-tocotrienol in tumor cells. Methods Murine B16 melanoma and human DU145 prostate carcinoma cells were incubated for 48 h (B16) or 72 h (DU145) with xanthorrhizol or d-δ-tocotrienol before cell populations were determined by CellTiter 96â Aqueous One Solution. Cells incubated with the agents for 24 hours were stained with propidium iodide and analyzed for cell cycle using flow cytometry and MultiCycle AV. Isobologram and combination index (CI) were used to demonstrate their synergistic anti-proliferative impacts. Results Xanthorrhizol (0–200 µmol/L) and d-δ-tocotrienol (0–40 µmol/L) each elicited a concentration-dependent suppression of the proliferation of B16 cells. A blend of 16.25 µmol/L xanthorrhizol and 10 µmol/L d-δ-tocotrienol achieved 69% (P < 0.05) growth suppression of B16 cells, exceeding the sum of individual effects. B16 cells incubated with 5 and 10 µmol/L d-δ-tocotrienol for 24-h had a concentration-dependent increase in the percentage of cells in the G1 phase with a concomitant decrease in the percentage of cells in the S phase. The G1/S ratio, an indicator of cell cycle arrest at the G1 phase, increased from 1.73 ± 0.05 (Control) to 2.01 ± 0.10 (5 µmol/L) and 2.73 ± 0.05 (10 µmol/L). A parallel pattern of concentration-dependent increase in the G1/S ratio was induced by xanthorrhizol at concentrations equivalent to 25% (16.25 µmol/L) and 50% (32.5 µmol/L) of its IC50 value. A blend of 5 µmol/L d-δ-tocotrienol and 16.25 µmol/L xanthorrhizol, each at no-effect concentrations, significantly increased the percentage of B16 cells in the G1 phase to 62.6 ± 0.6%. Isobologram and CI confirmed the synergistic effect of xanthorrhizol (50 and 100 μmol/L) and d-δ-tocotrienol (10 and 20 μmol/L) on the proliferation of DU145 cells. Conclusions Xanthorrhizol and d-δ-tocotrienol synergistically suppress tumor cell proliferation by inducing G1 arrest and may have potential in cancer prevention and therapy. Funding Sources American River Nutrition, Inc. and the University Assistantship Program and the Department of Nutrition of Georgia State University.