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Garlic, an Allium vegetable, contains rich flavonoids organosulfur compounds (OSCs) that have potent anticancer properties. The aim of the review is to provide an overview of the different types of garlic, their active compounds, and the potential anticancer benefits with a focus on antioxidant activity. Animal and cell line studies have provided convincing evidence that garlic and its organosulfur compounds inhibit carcinogenesis through a number of events including induction of apoptosis, inhibiting cellular proliferation, scavenging radical oxygen species (ROS), increasing the activities of enzymes such as glutathione S-transferase, and reducing tumor size. Epidemiological studies showed compelling evidence that garlic consumption is associated with decreased risk of colorectal cancer, but inconsistent evidence for stomach, breast, and prostate cancers. Studies also suggest that the presence and potency of garlic OSCs varies with respect to the preparation and form of garlic. Further epidemiological studies with information on garlic form consumed or preparation methods and molecular studies regarding its antioxidant mechanisms, such as increasing enzymatic and nonenzymatic antioxidants levels, are warranted.

Benzaldehyde dimethane sulfonate (BEN, DMS612, NSC281612) is a bifunctional alkylating agent currently in clinical trials. We previously characterized the degradation products of BEN in plasma and blood. The conversion of BEN to its carboxylic acid analogue (BA) in whole blood, but not plasma, suggests that an enzyme in RBCs may be responsible for this conversion. BEN conversion to BA was observed in renal carcinoma cells and appeared to correlate with IC₅₀. To better understand the pharmacology of BEN, we aimed to evaluate the metabolism and enzymes potentially responsible for the conversion of BEN to BA.Human red blood cells (RBC) were used to characterize kinetics and susceptibility to enzyme-specific inhibitors. Recombinant enzymes were used to confirm metabolism of BEN to BA. Analytes were quantitated with established LC-MS/MS methods.Average apparent Vmax and Km were 68 ng/mL min(-1) [10% RBC](-1) and 373 ng/mL, respectively. The conversion of BEN to BA in RBC was not inhibited by carbon monoxide, nitrogen gas, or menadione, an inhibitor of aldehyde oxidase. The conversion was inhibited by disulfiram, an inhibitor of ALDH. Of available ALDH isoforms ALDH1A1, ALDH3A1, ALDH2, and ALDH5A1, only ALDH1A1 converted BEN to BA.The activating conversion of BEN to BA is mediated not by CYP450 enzymes or aldehyde oxidase, but by ALDH1A1. This enzyme, a potential stem cell marker, may be a candidate biomarker for clinical activity of BEN.

We have isolated from human breast cancers several mutations in the Helix 12 component of activation function 2 (AF-2) in the estrogen receptor alpha (ERalpha). We used a novel approach to detect changes in the hormone-binding domain of ERalpha, based on the evidence that antiestrogens, such as 4-hydroxytamoxifen (ZOHT) and ICI 182,780, block the function of ERalpha by binding and folding the AF-2 transcriptional domain in a way that inhibits its association with coactivator proteins. We have identified a Helix 12 mutation, M543V, which leads to greater ERalpha transcription with ZOHT and other antiestrogens (including 1,1-dichloro-2,2,3-triarylcyclopropanes, DTACs) than with 17-beta estradiol (E2). We also found an independent mutation at the same position, M543I, which did not show this inverted ligand phenotype. In comparison to further Helix 12 mutations made in vitro, it appears that relative hydrophobicity of the amino acid side chains on the inner face of Helix 12 is key to maintaining the transcriptionally active, agonist conformation with bound E2. This active conformation can be induced, resulting in increased transcription, by adding excess p160 coactivator AIB1 in transcriptional assays with E2-bound receptors, while the ZOHT-bound receptors were not further activated by AIB1. Other experiments show that the cross talk between ERalpha and AP-1 protein from AP-1-binding sites is not dependent on Helix 12 integrity. We show that two alleles containing a proline substitution in Helix 12 that inactivate AF-2 function of ERalpha at EREs have little negative effect on function through AP-1 elements, supporting a prominent role for the N-terminal AF-1 of ERalpha in AP-1/ERalpha transcriptional cross talk.

Objectives The data reported are from a trial designed to determine, in patients with advanced cancer, the maximum tolerated dose and pharmacokinetics of calcitriol when administered with paclitaxel, an agent whose antitumor activity in in vitro and in vivo studies has been shown to be enhanced by calcitriol. An additional goal was to evaluate the relationship between calcitriol dose and hypercalcemia. Methods Calcitriol was given orally for 3 consecutive days each week, and paclitaxel (80 mg/m2) was given intravenously weekly. Thirty-six patients were treated in cohorts composed of 3 to 9 patients, at escalating dose levels of calcitriol. The starting dose of calcitriol was 4 μg for 3 consecutive days each week, and the maximum dose administered was 38 μg for 3 consecutive days each week. The preparation of calcitriol used in this trial was a commercially available caplet (0.5 μg per caplet). Serum calcitriol concentrations were measured by radioimmunoassay. Detailed assessments of calcitriol pharmacokinetics were performed in 26 patients. Results There was substantial interpatient variation in peak serum calcitriol concentrations (Cmax), time to reach Cmax, and area under the concentration versus time curve (AUC). Serum calcitriol AUC was not proportional to calcitriol dose (P = .0014). AUC for the 24-hour period after calcitriol administration [AUC (0–24)] at 38 μg was only 4 times that at 4 μg, instead of the 9.5-fold increase expected for a proportional relationship. Calcitriol plasma concentrations of 600 to 1440 pg/mL were achieved. No dose-limiting toxicity occurred in this trial. Conclusions Despite variability in absorption, very high doses of calcitriol can be safely administered with paclitaxel. The high calcitriol serum concentrations achieved in this study approach those that, both in vitro and in vivo, potentiate the cytotoxicity of taxanes and platinum analogs. Clinical Pharmacology & Therapeutics (2002) 72, 648–659; doi: 10.1067/mcp.2002.129305

Calcitriol or 1,25-dihydroxycholecalciferol (vitamin D) is classically known for its effects on bone and mineral metabolism. Epidemiological data suggest that low vitamin D levels increase the risk and mortality from prostate cancer. Calcitriol is also a potent anti-proliferative agent in a wide variety of malignant cell types including prostate cancer cells. In prostate model systems (PC-3, LNCaP, DU145, MLL) calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol’s effects are associated with an increase in cell cycle arrest, apoptosis, differentiation and in the modulation of growth factor receptors. Calcitriol induces asignificant Go/Gii arrest and modulates p21Waf1/Cip1 and p27Kip1, the cyclin dependent kinase inhibitors. Calcitriol induces PARP cleavage, increases the bax/bcl-2 ratio, reduces levels of phosphorylated mitogen-activated protein kinases (P-MAPKs, P-Erk-1/2) and phosphorylated Akt (P-Akt), induces caspase-dependent MEK cleavage and up-regula tion of MEKK-1, all potential markers of the apoptotic pathway. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. In combination with calcitriol, dexamethasone results in a significant time- and dose-dependent increase in VDR protein and an enhanced apoptotic response as compared to calcitriol alone. Calcitriol can also significantly increase cytotoxic drug-mediated anti-tumor efficacy. As a result, phase I and II trials of calcitriol either alone or in combination with the carboplatin, paclitaxel, or dexamethasone have been initiated in patients with androgen-dependent and -independent prostate cancer and advanced cancer. Patients were evaluated for toxicity, maximum tolerated dose (MTD), schedule effects, and PSA response. Data from these studies indicate that high-dose calcitriol is feasible on an intermittent schedule, the MTD is still being delineated and dexamethasone or paclitaxel appear to ameliorate toxicity. Studies continue to define the MTD of calcitriol which can be safely administered on this intermittent schedule either alone or with other agents and to evaluate the mechanisms of calcitriol effects in prostate cancer.

Introduction: Systemic sclerosis (SSc) is more prevalent in women. Our goal is to determine the effects of 17bestradiol (E2) on the development of fibrosis and to compare circulating levels of estrogens in SSc patients and healthy controls. Methods: Using primary human dermal fibroblasts, we evaluated the effect of E2 on fibronectin (FN) expression with and without the estrogen receptor (ER) antagonist ICI 182,780, inhibitors of signaling, propyl-pyrazole-triol, an ERa specific ligand, and genistein, an ERb selective ligand, to identify the signaling pathways mediating E2’s effect. We confirmed the fibrotic effect of E2 in human skin using an ex vivo organ culture model. Lastly, we measured levels of E2 and estrone in serum samples from SSc patients with diffuse cutaneous involvement and healthy controls using mass spectrometry. Results: E2 increased expression of FN in dermal fibroblasts. ICI 182,780, inositol-1,4,5-triphosphate inhibitor, and p38 mitogen-activated protein kinase inhibitor blocked the effects of E2 on FN. Propyl-pyrazole-triol, but not genistein, significantly increased FN expression. Ex vivo, E2 induced fibrosis of human skin. The effects of E2 were abrogated by ICI 182,780. Circulating levels of E2 and estrone were significantly increased in sera of patients with diffuse cutaneous SSc. Conclusion: Our findings implicate estrogens in the fibrotic process and may explain the preponderance of SSc in women. ICI 182,780 or other ER signaling antagonists may be effective agents for the treatment of fibrosis.