Biomedical subjects

Erum A Hussain

Publications and source records attributed to Erum A Hussain.

3 recordsLinked to original sources

PubMed2003

Efficacy and mechanism of action of 1alpha-hydroxy-24-ethyl-cholecalciferol (1alpha[OH]D5) in breast cancer prevention and therapy.

It is now well established that the active metabolite of vitamin D3, 1alpha,25(OH)2D3, regulates cell growth and differentiation in various in vitro cancer models. However, its clinical use is precluded due to its hypercalcemic activity in vivo. Hence, several less calcemic vitamin D analogs have been synthesized and evaluated for their chemopreventive and therapeutic efficacy in experimental carcinogenesis models. A novel analog of vitamin D3, 1alpha-hydroxy-24-ethyl-cholecalciferol (1alpha[OH]D5), has currently been under investigation in our laboratory for its application in breast cancer prevention and therapy. 1alpha(OH)D5 had been shown to inhibit development of estrogen- and progesterone-dependent ductal lesions as well as steroid hormone-independent alveolar lesions in a mammary gland organ culture (MMOC) model. Moreover, the inhibitory effect was more significant if 1alpha(OH)D5 was present during the promotional phase of the lesion development. The growth inhibitory effect of 1alpha(OH)D5 has also been manifested in several breast cancer cell lines, including BT-474 and MCF-7. Breast cancer cell lines that responded to 1alpha(OH)D5 treatment were vitamin D receptor positive (VDR+). Vitamin D receptor-negative (VDR-) cell lines, such as MDA-MB-231 and MDA-MB-435, did not show growth inhibition upon incubation with 1alpha(OH)D5. This suggests the requirement of VDR in 1alpha(OH)D5-mediated growth effects. Interestingly, breast cancer cells that were VDR+ as well as estrogen receptor positive (ER+) showed cell cycle arrest and apoptosis, while VDR+ but ER- cells (UISO-BCA-4 breast cancer cells) showed enhanced expression of various differentiation markers with la(OH)D5 treatment. Transcription and expression of estrogen-inducible genes, progesterone receptor (PR) and trefoil factor 1 (pS2), were significantly down-regulated in ER+ BT-474 cells with 1alpha(OH)D5 treatment. This implies a differential effect of 1alpha(OH)D5 on ER+ vs. ER- cells. Additionally, comparison between the effects of 1alpha(OH)D5 on normal vs. transformed cells indicated that 1alpha(OH)D5 does not suppress cell prolifera-

Animals↗

PubMed2002

Esterification does not impair lutein bioavailability in humans.

Age-related macular degeneration (ARMD) is inversely associated with the accumulation of lutein + zeaxanthin in the macula, but higher lutein intakes are inconsistently related to reduced risk of ARMD in epidemiologic studies. Resolution of efficacy awaits clinical trials designed with knowledge of lutein supplement pharmacokinetics. Lutein bioavailability was determined for lutein diester and unesterified lutein formulations as they might be incorporated into dietary supplements. Healthy subjects (n = 18) consumed a single dose of each formulation (either 0.5 or 0.67 micro mol lutein/kg body, 10 and 8 subjects, respectively) in random order, and the appearance of free lutein + zeaxanthin was measured in serum from 0 to 408 h. Areas under the serum concentration x time curves (AUC), as a measure of bioavailability, were independent of gender, body mass index and lutein dose. The lutein diester formulation was 61.6% more bioavailable than the unesterified lutein formulation with higher mean AUC, maximum serum concentration and ascending slope (P < 0.05). The AUC was greater in 14 of 18 subjects when they consumed the lutein diester formulation. Comparison with data from previous studies suggested that dissolution was a greater limitation to bioavailability than lutein ester hydrolysis because an oil-solubilized unesterified lutein preparation, given at 0.5 micro mol/kg body, resulted in greater mean peak concentrations and AUC compared with either the unesterified or lutein diester formulations used in our study. In conclusion, the lutein diester formulation poses no impediment to lutein bioavailability at the doses tested, but formulation dissolution is an important factor in lutein bioavailability and should be evaluated before a supplement and dose are selected for use in clinical trials.

Adult↗

PubMedDate not supplied

Chemoprevention of mammary carcinogenesis by 1alpha-hydroxyvitamin D5, a synthetic analog of Vitamin D.

Numerous analogs of Vitamin D have been synthesized in recent years with the hope of generating a compound that retains the anticarcinogenic activity of Vitamin D without causing any toxicity. We synthesized such an analog, 1alpha-hydroxy-24-ethylcholecalciferol [1alpha-hydroxyvitamin D(5) or 1alpha(OH)D(5)], and showed that it was tolerated by rats and mice at a much higher dose than 1alpha,25 dihydroxy cholecalciferol [1alpha,25(OH)(2)D(3)]. This property makes it a prime candidate for chemoprevention studies. In the mouse mammary gland organ culture (MMOC), 1alpha(OH)D(5) inhibited carcinogen-induced development of both mammary alveolar and ductal lesions. In vivo carcinogenesis study showed statistically significant reduction of tumor incidence and multiplicity in N-methyl-N-nitrosourea (MNU)-treated rats that were fed 25-50 microg 1alpha(OH)D(5)/kg diet. There were no adverse effects on plasma calcium concentrations. In order to determine if the effect of 1alpha(OH)D(5) would be selective in suppressing proliferation of transformed cells, its effects on cell growth and proliferation were compared between BT474 (cancer) and MCF12F (non-tumorigenic) human breast epithelial cells. Results showed that 1alpha(OH)D(5) induced apoptosis and cell cycle G1 phase arrest in BT474 breast cancer cells without having any effects on proliferation of the MCF12F cells. In addition, in MMOC it had no growth inhibitory effects on normal epithelial cell proliferation in the absence of carcinogen. Similarly, non-tumorigenic human breast epithelial cells in explant culture did not respond to 1alpha(OH)D(5), whereas treatment with 1alpha(OH)D(5) induced cell death in the explants of cancer tissue. These results collectively indicate that 1alpha(OH)D(5) selectively induced apoptosis only in transformed cells but not in normal breast epithelial cells. Interestingly, the growth inhibitory effects of 1alpha(OH)D(5) were observed in Vitamin D receptor positive (VDR(+)) breast cancer cells, but not in highly metastatic VDR(-) breast cancer cells, such as MDA-MB-435 and MDA-MB-231, suggesting that 1alpha(OH)D(5) action may be mediated, in part, by VDR.

9,10-Dimethyl-1,2-benzanthracene↗