1α,25-Dihydroxyvitamin D3 (calcitriol) and its analogue, 19-nor-1α,25(OH)2D2, potentiate the effects of ionising radiation on human prostate cancer cells

Dunlap, Neal E.; Schwartz, Gary G.; Eads, Dawn; Cramer, Scott D.; Sherk, Andrea B.; John, Vishak J.; Koumenis, Constantinos

doi:10.1038/sj.bjc.6601161

Cited by 61 publications

(33 citation statements)

References 44 publications

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“…It has been hypothesised that vitamin D can amplify the effect of cancer treatment; a synergistic effect that has been observed in both experimental and clinical studies (Dunlap et al, 2003;Deeb et al, 2007). Furthermore, results from experimental studies also indicate an interaction between sexual hormones and vitamin D metabolism (Nyomba et al, 1987;Sarem and Pedersen, 1988;Bolland et al, 2007).…”

Section: Discussionmentioning

confidence: 84%

“…A recent study by Ahn et al (2008) shows that a high circulating 25(OH)D level may be associated with an increased risk (Schwartz, 2005). Several experimental studies have demonstrated the anti-invasive and anti-metastatic effect of vitamin D on prostate cells, through its promotion of differentiation and apoptosis and its inhibiting effect on angiogenesis and proliferation (see Dunlap et al, 2003). Our results are consistent with the ecological studies showing the lowest death risk among patients diagnosed in seasons with high ultraviolet radiation exposure (Robsahm et al, 2004;Lim et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

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Association between serum 25(OH)D and death from prostate cancer

et al. 2009

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Based on observations that for certain cancers, mortality varies according to sun exposure, vitamin D has been proposed to influence on disease progression. This study aims to investigate whether serum levels of 25(OH)D are associated with prognosis in patients with prostate cancer. In total, 160 patients with a serum sample in the JANUS serum bank were included. For 123 patients a pretreatment serum sample was taken, whereas 37 of the patients had received hormone therapy prior to the blood collection. The serum level of 25(OH)D was classified as low (o 50 nmol l À1 ), medium (50 -80 nmol l À1 ) or high (480 nmol l À1 ). A Cox proportional hazard regression model was used to assess the association between serum 25(OH)D and cancer mortality. During follow-up, 61 deaths occurred, of whom 52 died of prostate cancer. The median time of follow-up was 44.0 months (range, 1.2 -154.6). Serum 25(OH)D at medium or high levels were significantly related to better prognosis (RR 0.33; 95% CI 0.14 -0.77, RR 0.16; 95% CI 0.05 -0.43) compared with the low level. Analysis restricted to patients receiving hormone therapy gave a stronger association. The serum level of 25(OH)D may be involved in disease progression and is a potential marker of prognosis in patients with prostate cancer.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Association between serum 25(OH)D and death from prostate cancer

et al. 2009

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“…37). Importantly, paricalcitol did not induce significant radiosensitization of normal prostate epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Phase I/II Study of 19-nor-1α-25-Dihydroxyvitamin D2 (Paricalcitol) in Advanced, Androgen-Insensitive Prostate Cancer

Schwartz¹,

Hall

Stindt

et al. 2005

Clinical Cancer Research

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Purpose: We assessed the safety and efficacy of the vitamin D analogue, 19-nor-1a-25-dihydroxyvitamin D 2 (paricalcitol), in patients with androgen-independent prostate cancer. Experimental Design: Patients received paricalcitol i.v. three times per week on an escalating dose of 5 to 25 Ag (3-15 Ag/m 2 ). The primary end point was prostate-specific antigen (PSA) response. Secondary end points were characterization of toxicity in this population, changes in serum parathyroid hormone (PTH), and survival. Results: A total of 18 patients were enrolled. No patient showed a sustained 50% drop in serum PSA, despite several large declines in PSA (e.g., 1,300 ng/mL). Paricalcitol was well tolerated. One instance of significant hypercalcemia, a serum calcium of 14.3 mg/dL, was observed at the highest dose (25 Ag). At entry into the study, seven (41%) of the patients had elevated serum levels of PTH, which were significantly reduced by paricalcitol. Higher levels of serum PTH at study entry were significantly and negatively associated with survival (P < 0.01). Conclusion:No objective responses were seen in the primary end point. However, elevated serum levels of PTH, a common feature of advanced prostate cancer, were reduced by paricalcitol. Because elevated PTH is associated with increased cardiovascular and skeletal morbidity, including an increased risk for pathologic fracture, further evaluation of paricalcitol in the reduction of skeletal morbidity in advanced prostate cancer is warranted. Prostate cancer is the most prevalent (nonskin) cancer amongAmerican men and the second most fatal, accounting for >30,000 deaths in 2005 (1). For men with advanced disease, the mainstay of prostate cancer therapy is androgen withdrawal. Although androgen withdrawal is usually effective in lowering prostate-specific antigen (PSA) in men with prostate cancer, in men with metastatic disease, the duration of response is brief (about 14-18 months), and androgen-independent prostate cancer (AIPC) supervenes in virtually all treated men. The median survival once AIPC develops is 12 to 18 months. Although recent clinical trials in AIPC have shown a survival benefit for docetaxel-based chemotherapy, the benefit is modest (about 2 months; refs. 2, 3). Thus, new therapies for AIPC are urgently needed (4, 5).Considerable attention has focused on the role of vitamin D in prostate cancer, stemming from the observation by Schwartz and Hanchette that mortality rates from prostate cancer are inversely related to levels of UV radiation, the major source of vitamin D (6). Vitamin D is synthesized in response to sunlight and undergoes hydroxylation in the liver to 25-hydroxyvitamin D (calcidiol) and then in the kidney to form 1,25-dihydroxyvitamin D (calcitriol), the hormonal form of vitamin D. Extensive research has shown that prostate cells, including prostate cancer cells, express specific receptors (VDR) for 1,25-dihydroxyvitamin D. When bound to the VDR, 1,25-dihydroxyvitamin D regulates >60 genes that exert prodifferentiating, antiproli...

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“…[204][205][206] There are several reports that calcitriol, as well as other agonists for the vitamin D receptor that are less calcemic, can boost the apoptotic response to radiation in human prostate and breast cancer cell lines, in concentrations that in themselves have little impact on spontaneous apoptosis. [207][208][209][210] This effect might be mediated by modulation of the expression of members of the bcl-2 family, [211][212][213][214][215][216] whose expression is known to have a major impact on cellular radiosensitivity. [217][218][219][220][221][222] A least a portion of this effect might be secondary to increased production of IGFBP-3, which, through mechanisms that are independent of IGF-I, can boost expression of proapoptotic Bax and Bad while suppressing expression (or activity) of antiapoptotic bcl-2 and bcl-xL in certain cell lines.…”

Section: Multifocal Signal Modulation Therapies As Adjuvants To Cytotmentioning

confidence: 99%

Preadministration of High-Dose Salicylates, Suppressors of NF-κB Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy

McCarty

Block

2006

Integr Cancer Ther

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NF-κB activity is elevated in a high proportion of cancers, particularly advanced cancers that have been treated previously. Cytotoxic treatment selects for such up-regulation inasmuch as NF-κB promotes transcription of a large number of proteins that inhibit both the intrinsic and extrinsic pathways of apoptosis; NF-κB also boosts expression of mdr1, which expels many drugs from cells. Indeed, high NF-κB activity appears to be largely responsible for the chemo-and radioresistance of many cancers. Thus, agents that suppress NF-κB activity should be useful as adjuvants to cytotoxic cancer therapy. Of the compounds that are known to be NF-κB antagonists, the most practical for current use may be the nonsteroidal anti-inflammatory drugs aspirin, salicylic acid, and sulindac, each of which binds to and inhibits IκB kinase-β, a central mediator of NF-κB activation; the low millimolar plasma concentrations of salicylate required for effective inhibition of this kinase in vivo can be achieved with highdose regimens traditionally used to manage rheumatic disorders. The gastrointestinal toxicity of such regimens could be minimized by using salsalate or enteric-coated sodium salicylate or by administering misoprostol in conjunction with aspirin therapy. Presumably, best results would be seen if these agents were administered for several days prior to a course of chemo-or radiotherapy, continuing throughout the course. This concept should first be tested in nude mice bearing xenografts of chemoresistant human tumors known to have elevated NF-κB activity. Ultimately, more complex adjuvant regimens can be envisioned in which salicylates are used in conjunction with other NF-κB antagonists and/or agents that target other mediators of down-regulated apoptosis in cancer, such as Stat3; coadministration of salicylate and organic selenium may have intriguing potential in this regard. These strategies may also have potential as adjuvants to metronomic chemotherapy, which seeks to suppress angiogenesis by targeting cycling endothelial cells in tumors.

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1α,25-Dihydroxyvitamin D3 (calcitriol) and its analogue, 19-nor-1α,25(OH)2D2, potentiate the effects of ionising radiation on human prostate cancer cells

Cited by 61 publications

References 44 publications

Association between serum 25(OH)D and death from prostate cancer

Association between serum 25(OH)D and death from prostate cancer

Phase I/II Study of 19-nor-1α-25-Dihydroxyvitamin D2 (Paricalcitol) in Advanced, Androgen-Insensitive Prostate Cancer

Preadministration of High-Dose Salicylates, Suppressors of NF-κB Activation, May Increase the Chemosensitivity of Many Cancers: An Example of Proapoptotic Signal Modulation Therapy

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