Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020437 (hypercalcemia)
 10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rickets is seen in association with vitamin D deficiency and in several genetic disorders associated with abnormal mineral ion homeostasis. Studies in vitamin D receptor (VDR)-null mice have demonstrated that expansion of the late hypertrophic chondrocyte layer, characteristic of rickets, is secondary to impaired apoptosis of these cells. The observation that normalization of mineral ion homeostasis in the VDR-null mice prevents rachitic changes suggests that rickets is secondary to hypocalcemia, hypophosphatemia, or hyperparathyroidism, rather than impaired VDR action. To determine which of these abnormalities is responsible for impaired chondrocyte apoptosis and subsequent rachitic changes, two additional models were examined: diet-induced hypophosphatemia/hypercalcemia and hypophosphatemia secondary to mutations in the Phex gene. The former model is associated with suppressed parathyroid hormone levels as a consequence of hypercalcemia. The latter model demonstrates normal calcium and parathyroid hormone levels, but 1,25-dihydroxyvitamin D levels that are inappropriately low for the degree of hypophosphatemia. Our studies demonstrate that normal phosphorus levels are required for growth plate maturation and implicate a critical role for phosphate-regulated apoptosis of hypertrophic chondrocytes via activation of the caspase-9-mediated mitochondrial pathway.
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PMID:Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. 1597 27

The role of vitamin D3 in cancer prevention and its potential as an anticancer therapeutic agent have been researched and are well established. However, the clinical use of the natural vitamin D3 metabolite, 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3 or calcitriol] is limited by a possible cause of hypercalcemia and hypercalciuria. A new 24-chloro calcipotriene-based vitamin D3 analog (BGP-15) was synthesized and examined for antiproliferative activity in the androgen-dependent cell lines of prostate cancer (LNCaP) and breast cancer (MCF-7). The new analog led to significant decrease in cell viability in cultured LNCaP and MCF-7 cell lines compared with calcipotriene and 1,25(OH)2D3. We observed elevated vitamin D receptor protein levels in both LNCaP and MCF-7 cells, which were treated with 5 micromol/l of 1,25(OH)2D3, calcipotriene or BGP-15 for 20 h, indicating vitamin D receptor-binding ability. Treatments of LNCaP and MCF-7 cells with 5 micromol/l BGP-15 and calcipotriene for 20 h generated procaspase-3 cleavage and therefore, apoptosis. Interestingly, BGP-15, and to a lesser extent calcipotriene, but not 1,25(OH)2D3, activated caspase-3 in MCF-7 cells, a cell line that normally lacks this specific caspase (and procaspase). It is presumed that management of MCF-7 with BGP-15 modulates procaspase-3 expression and cleavage, and a subsequent activation of caspase-3. Similar treatments of LNCaP cells induced procaspase-9 cleavage and therefore caspase-9 activation, whereas similar treatments of MCF-7 cells failed to induce caspase-9 activation. Cytochrome c release was, however, detected in both cell lines, LNCaP and MCF-7. In-vivo results suggested that BGP-15 (similar to its parent drug) did not cause calcium-related toxic side effects after chronic treatment.
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PMID:Induction of apoptosis and inhibition of prostate and breast cancer growth by BGP-15, a new calcipotriene-derived vitamin D3 analog. 2033 94

High systemic exposures to calcitriol are necessary for optimal antitumor effects. Human prostate cancer PC3 cells are insensitive to calcitriol treatment. Therefore, we investigated whether the inhibition of 24-hydroxylase (CYP24A1), the major calcitriol inactivating enzyme, by ketoconazole (KTZ) or RC2204 modulates calcitriol serum pharmacokinetics and biologic effects. Dexamethasone (Dex) was added to minimize calcitriol-induced hypercalcemia and as a steroid replacement for the KTZ inhibition of steroid biosynthesis cytochrome P450 enzymes. KTZ effectively inhibited time-dependent calcitriol-inducible CYP24A1 protein expression and enzyme activity in PC3 cells and C3H/HeJ mouse kidney tissues. Systemic calcitriol exposure area under the curve was higher in mice treated with a combination of calcitriol and KTZ than with calcitriol alone. KTZ and Dex synergistically potentiated calcitriol-mediated antiproliferative effects in PC3 cells in vitro; this effect was associated with enhanced apoptosis. After treatment with calcitriol and KTZ/Dex, although caspase-9 and caspase-3 were not activated and cytochrome c was not released by mitochondria, caspase-8 was activated and the truncated Bid protein level was increased. Translocation of apoptosis-inducing factor to the nucleus was observed, indicating a role of the apoptosis-inducing factor-mediated and caspase-independent apoptotic pathways. Calcitriol and KTZ/Dex combination suppressed the clonogenic survival and enhanced the growth inhibition observed with calcitriol alone in PC3 human prostate cancer xenograft mouse model. Our results show that the administration of calcitriol in combination with CYP24A1 inhibitor enhances antiproliferative effects, increases systemic calcitriol exposure, and promotes the activation of caspase-independent apoptosis pathway.
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PMID:CYP24A1 inhibition enhances the antitumor activity of calcitriol. 2059 73

Parathyroid hormone-related protein (PTHrP) is a key component in breast development and breast tumour biology. PTHrP has been discovered as a causative agent of hypercalcaemia of malignancy and is also one of the main factors implicated in breast cancer mediated osteolysis. Clinical studies have determined that PTHrP expression by primary breast cancers was an independent predictor of improved prognosis. Furthermore, PTHrP has been demonstrated to cause tumour cell death both in vitro and in vivo. Apo2L/TRAIL is a promising new anti-cancer agent, due to its ability to selectively induce apoptosis in cancer cells whilst sparing most normal cells. However, some cancer cells are resistant to Apo2L/TRAIL-induced apoptosis thus limiting its therapeutic efficacy. The effects of PTHrP on cell death signalling pathways initiated by Apo2L/TRAIL were investigated in breast cancer cells. Expression of PTHrP in Apo2L/TRAIL resistant cell line MCF-7 sensitised these cells to Apo2L/TRAIL-induced apoptosis. The actions of PTHrP resulted from intracellular effects, since exogenous treatment of PTHrP had no effect on Apo2L/TRAIL-induced apoptosis. Apo2L/TRAIL-induced apoptosis in PTHrP expressing cells occurred through the activation of caspase-10 resulting in caspase-9 activation and induction of apoptosis through the effector caspases, caspase-6 and -7. PTHrP increased cell surface expression of Apo2L/TRAIL death receptors, TRAIL-R1 and TRAIL-R2. Antagonistic antibodies against the death receptors demonstrated that Apo2L/TRAIL mediated its apoptotic signals through activation of the TRAIL-R2 in PTHrP expressing breast cancer cells. These studies reveal a novel role for PTHrP with Apo2L/TRAIL that maybe important for future diagnosis and treatment of breast cancer.
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PMID:PTHrP Overexpression Increases Sensitivity of Breast Cancer Cells to Apo2L/TRAIL. 2382 95