Complex polymorphisms in endocytosis genes suggest alpha-cyclodextrin as a treatment for breast cancer.

Most breast cancer deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs, which have severe side effects, and hormonal treatments, which are or become ineffective for many patients, are urgently needed. This study reanalyzed existing data from three genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in studies of 600-2000 subjects in epilepsy and autism. MuGWAS jointly analyzes several neighboring single nucleotide polymorphisms while incorporating knowledge about genetics of heritable diseases into the statistical method and about GWAS into the rules for determining adaptive genome-wide significance. Results from three independent GWAS of 1000-2000 subjects each, which were made available under the National Institute of Health's "Up For A Challenge" (U4C) project, not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in breast cancer GWAS, also consistently identified many genes involved in endo-/exocytosis (EEC), most of which had already been observed in functional and expression studies of breast cancer. In particular, the findings include genes that translocate (ATP8A1, ATP8B1, ANO4, ABCA1) and metabolize (AGPAT3, AGPAT4, DGKQ, LPPR1) phospholipids entering the phosphatidylinositol cycle, which controls EEC. These novel findings suggest scavenging phospholipids as a novel intervention to control local spread of cancer, packaging of exosomes (which prepare distant microenvironment for organ-specific metastases), and endocytosis of ß1 integrins (which are required for spread of metastatic phenotype and mesenchymal migration of tumor cells). Beta-cyclodextrins (ßCD) have already been shown to be effective in in vitro and animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller alpha-cyclodextrins (αCD) also scavenges phospholipids, but cannot fit cholesterol. An in-vitro study presented here confirms hydroxypropyl (HP)-αCD to be twice as effective as HPßCD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer. If the previous successful animal studies with ßCDs are replicated with the safer and more effective αCDs, clinical trials of adjuvant treatment with αCDs are warranted. Ultimately, all breast cancer are expected to benefit from treatment with HPαCD, but women with triple-negative breast cancer (TNBC) will benefit most, because they have fewer treatment options and their cancer advances more aggressively.

Dietary α-cyclodextrin reduces atherosclerosis and modifies gut flora in apolipoprotein E-deficient mice.

SCOPE: α-Cyclodextrin (α-CD), a cyclic polymer of glucose, has been shown to lower plasma cholesterol in animals and humans; however, its effect on atherosclerosis has not been previously described. METHODS AND RESULTS: apoE-knockout mice were fed either low-fat diet (LFD; 5.2% fat, w/w), or Western high fat diet (21.2% fat) containing either no additions (WD), 1.5% α-CD (WDA); 1.5% ß-CD (WDB); or 1.5% oligofructose-enriched inulin (WDI). Although plasma lipids were similar after 11 weeks on the WD vs. WDA diets, aortic atherosclerotic lesions were 65% less in mice on WDA compared to WD (P < 0.05), and similar to mice fed the LFD. No effect on atherosclerosis was observed for the other WD supplemented diets. By RNA-seq analysis of 16S rRNA, addition of α-CD to the WD resulted in significantly decreased cecal bacterial counts in genera Clostridium and Turicibacterium, and significantly increased Dehalobacteriaceae. At family level, Comamonadaceae significantly increased and Peptostreptococcaceae showed a negative trend. Several of these bacterial count changes correlated negatively with % atherosclerotic lesion and were associated with increased cecum weight and decreased plasma cholesterol levels. CONCLUSION: Addition of α-CD to the diet of apoE-knockout mice decreases atherosclerosis and is associated with changes in the gut flora.

Stabilized sulforaphane for clinical use: Phytochemical delivery efficiency.

SCOPE: The isothiocyanate sulforaphane (SF) from broccoli is one of the most potent known inducers of the cytoprotective phase 2 response. Its role in a host of biochemical pathways makes it a major component of plant-based protective strategies for enhancing healthspan. Many nutritional supplements are now marketed that purport to contain SF, which in plants exists as a stable precursor, a thioglucoside hydroxysulfate. However, SF in pure form must be stabilized for use in supplements. METHODS AND RESULTS: We evaluated the stability and bioavailability of two stabilized SF preparations-an α-cyclodextrin inclusion (SF-αCD), and an SF-rich, commercial nutritional supplement. SF-αCD area-under-the-curve peak serum concentrations occurred at 2 h, but six of ten volunteers complained of mild stomach upset. After topical application it was not effective in upregulating cytoprotective enzymes in the skin of SKH1 mice whereas pure SF was effective in doing so. Both of these "stabilized" SF preparations were as potent as pure SF in inducing the cytoprotective response in cultured cells, and they were more stable and as bioavailable. CONCLUSION: Our studies of a stabilized phytochemical component of foods should encourage further examination of similar products for their utility in chronic disease prevention and therapy.

The oligosaccharide α-cyclodextrin has modest effects to slow gastric emptying and modify the glycaemic response to sucrose in healthy older adults.

In healthy older subjects, the glycaemic response to carbohydrate-containing meals is dependent on gastric emptying and intestinal absorption; when the latter is slowed, the magnitude of the rise in glucose is attenuated. The oligosaccharide α-cyclodextrin has been reported to diminish the glycaemic response to starch in young adults; this effect has been attributed to the inhibition of pancreatic amylase. We examined the effects of α-cyclodextrin on gastric emptying of, and the glycaemic and insulinaemic responses to, oral sucrose in healthy older subjects; as sucrose is hydrolysed by intestinal disaccharides, any effect(s) of α-cyclodextrin would not be attributable to amylase inhibition. A total of ten subjects (seven males and three females, age 68-76 years) were studied on 2 d. Gastric emptying, blood glucose and serum insulin were measured after ingestion of a 300 ml drink containing 100 g sucrose, labelled with (99m)Tc-sulphur colloid, with or without 10 g α-cyclodextrin. Gastric emptying was slowed slightly by α-cyclodextrin; this effect was evident between 135 and 195 min and was associated with a slight increase (P < 0·05) in distal stomach retention. After α-cyclodextrin, blood glucose was slightly less (P < 0·05) at 60 min, and serum insulin was less (P < 0·0005) at 90 and 120 min. There was no difference in the incremental areas under the curve (iAUC) for blood glucose, but there was a trend for the iAUC for serum insulin to be lower (P = 0·09) after α-cyclodextrin. We conclude that in a dose of 10 g, α-cyclodextrin has modest effects to slow gastric emptying of, and modify the glycaemic and insulinaemic responses to, oral sucrose, probably due to delayed intestinal carbohydrate absorption.

Biodegradation of cyclodextrins in soil.

Cyclodextrins, especially random methylated betaCD (RAMEB) and hydroxypropyl betaCD (HPbetaCD), are becoming common enhancing additives in the bioremediation of soils formerly contaminated by hydrocarbons and/or other poorly bioavailable organic pollutants. Therefore, their degradation in the soil, particularly the most persistent RAMEB, has been of great concern. Like oil contaminants, these additives should be biodegradable via an environmentally safe technology. Hence, in this paper, the biodegradability of eight different cyclodextrins (CDs) in four different soils was examined under various treatment conditions in laboratory and pilot scale field experiments. This paper is the first report on the potential biological fate of CDs studied under a large variety of environmental conditions and in different soil ecosystems. Data on the potential relationship between CD biodegradation and the biological removal of hydrocarbons in the CD-amended contaminated soils are also given. All CDs were found to be more or less biodegradable; even the most persistent RAMEB was depleted from soils under favourable conditions. In the field experiments, the depletion of RAMEB to about 40% of its initial level was observed for a period of 2 years in hydrocarbon-contaminated soils of high organic matter and cell concentration.