cholesterol-alpha-oxide and Neoplasms

In the nineteen sixties it was proposed that cholesterol might be involved in the etiology of cancers and cholesterol oxidation products were suspected of being causative agents. Researchers had focused their attention on cholesterol-5,6-epoxides (5,6-ECs) based on several lines of evidence: 1) 5,6-ECs contained an oxirane group that was supposed to confer alkylating properties such as those observed for aliphatic and aromatic epoxides. 2) cholesterol-5,6-epoxide hydrolase (ChEH) was induced in pre-neoplastic lesions of skin from rats exposed to ultraviolet irradiations and ChEH was proposed to be involved in detoxification processes like other epoxide hydrolases. However, 5,6-ECs failed to induce carcinogenicity in rodents which ruled out a potent carcinogenic potential for 5,6-ECs. Meanwhile, clinical studies revealed an anomalous increase in the concentrations of 5,6β-EC in the nipple fluids of patients with pre-neoplastic breast lesions and in the blood of patients with endometrious cancers, suggesting that 5,6-ECs metabolism could be linked with cancer. Paradoxically, ChEH has been recently shown to be totally inhibited by therapeutic concentrations of tamoxifen (Tam), which is one of the main drugs used in the hormonotherapy and the chemoprevention of breast cancers. These data would suggest that the accumulation of 5,6-ECs could represent a risk factor, but we found that 5,6-ECs were involved in the induction of breast cancer cell differentiation and death induced by Tam suggesting a positive role of 5,6-ECs. These observations meant that the biochemistry and the metabolism of 5,6-ECs needed to be extensively studied. We will review the current knowledge and the future direction of 5,6-ECs chemistry, biochemistry, metabolism, and relationship with cancer.

Topics: Animals; Cholesterol; Humans; Neoplasms; Terminology as Topic

Cholesterol epoxide hydrolase (ChEH) catalyzes the hydration of cholesterol-5,6-epoxides (5,6-EC) into cholestane-3β,5α,6β-triol. ChEH is a hetero-oligomeric complex called the anti-estrogen binding site (AEBS) comprising 3β-hydroxysterol-Δ(8)-Δ(7)-isomerase (D8D7I) and 3β-hydroxysterol-Δ(7)-reductase (DHCR7). D8D7I and DHCR7 regulate cholesterol biosynthesis, fetal development and growth, tumor cell differentiation and death. The un-reactivity of 5,6-EC toward nucleophiles has recently been demonstrated indicating that 5,6-EC are not alkylating and carcinogenic agents as first postulated. Here we discuss recent advances in the molecular characterization of ChEH, its potential role in cancer progression and resistance as well as the interest of inhibiting ChEH and to accumulate 5,6-EC which may contribute to the anti-tumor and chemopreventive action of ChEH inhibitors used in the clinic such as tamoxifen.

Topics: Animals; Antineoplastic Agents, Hormonal; Cholestanols; Cholesterol; Disease Progression; Drug Resistance, Neoplasm; Epoxide Hydrolases; Humans; Neoplasms; Tamoxifen

Experimental evidence indicates a relationship between cholesterol alpha-epoxide and skin cancer, and exposure of skin fibroblasts to ultraviolet radiation enduces formation of significant levels of this oxide. Colon cancer is also etiologically linked to cholesterol oxidation products. Higher than normal levels of cholestanetriol have been found in patients with colon cancer and also in those with precancerous disorders such as adenomatous polyps and ulcerative colitis. Higher than normal levels of cholesterol alpha-epoxide have been found in breast fluid aspirates of women with benign breast disease, with or without atypical hyperplasia of the epithelium, and this may be a factor in the increased incidence of breast cancer associated with hyperplasia. Similarly, the observed increased levels of cholesterol alpha and beta-epoxides in prostatic fluid of men with benign prostatic hypertrophy may be associated with subsequent development of prostate cancer. Cholesterol alpha-epoxide has been found to be mutagenic to fibroblasts in culture and to induce morphological transformation in hamster embryo cells and in mouse C3H cells. 25-Hydroxycholesterol and 20 alpha-hydroxycholesterol are potent suppressors of generation and proliferation of tumor-specific cytotoxic T lymphocytes. Although investigations into the role of cholesterol oxidation products in cancer are still in the early stages, evidence to date indicates a potentially significant role in the induction of some types of cancer.

Topics: Animals; Biotransformation; Carcinogens; Cholesterol; Cholesterol, Dietary; Humans; Neoplasms; Neoplasms, Experimental

We describe here the syntheses and the biological properties of new alkylaminooxysterols. Compounds were synthesized through the trans-diaxial aminolysis of 5,6-alpha-epoxysterols with various natural amines including histamine, putrescine, spermidine, or spermine. The regioselective synthesis of these 16 new 5alpha-hydroxyl-6beta-aminoalkylsterols is presented. Compounds were first screened for dendrite outgrowth and cytotoxicity in vitro, and two leads were selected and further characterized. 5alpha-Hydroxy-6beta-[2-(1H-imidazol-4-yl)ethylamino]cholestan-3beta-ol, called dendrogenin A, induced growth control, differentiation, and the death of tumor cell lines representative of various cancers including metastatic melanoma and breast cancer. 5alpha-Hydroxy-6beta-[3-(4-aminobutylamino)propylamino]cholest-7-en-3beta-ol, called dendrogenin B, induced neurite outgrowth on various cell lines, neuronal differentiation in pluripotent cells, and survival of normal neurones at nanomolar concentrations. In summary, we report that two new alkylaminooxysterols, dendrogenin A and dendrogenin B, are the first members of a class of compounds that induce cell differentiation at nanomolar concentrations and represent promising new leads for the treatment of cancer or neurodegenerative diseases.

Topics: Amines; Animals; Cell Differentiation; Cell Line, Tumor; Cell Survival; Cholestanols; Dendrites; Drug Discovery; Humans; Mice; Neoplasms; Neurodegenerative Diseases; Spermidine; Stereoisomerism; Sterols