title: Combination of calcitriol and dietary soy exhibits enhanced anticancer activity and increased hypercalcemic toxicity in a mouse xenograft model of prostate cancer.
abstract: BACKGROUND
  The potential role of vitamin D and soy in prostate cancer (PCa) prevention/treatment has gained much attention in recent years. In this study, we evaluated the anticancer activity of calcitriol, the active form of vitamin D, dietary soy, and their combinations in a mouse model of PCa.
  
  
  METHODS
  Athymic male nude mice bearing PC-3 human PCa xenografts received diets containing 10 or 20 kcal% soy, calcitriol injections, or a combination of dietary soy and calcitriol. Changes in tumor growth, serum levels of 1,25(OH)(2)D and calcium, and regulation of tumor gene expression were examined.
  
  
  RESULTS
  The combination treatments resulted in substantially greater inhibition of tumor growth than either agent alone. Soy diets alone caused a modest elevation in serum 1,25(OH)(2)D, whereas the calcitriol-soy combinations led to substantially elevated serum 1,25(OH)(2) D, hypercalcemia, and in some cases lethal toxicity. The combinations enhanced calcitriol activity in regulating target gene expression, including greater up-regulation of anti-proliferative (p21, IGFBP-3) and pro-apoptotic (Bax) genes, increased inhibition of anti-apoptotic (Bcl-2) and cell cycle promoting (cyclin D1) genes, and suppression of prostaglandin (PG) synthesis and signaling (COX-2, 15-PGDH, PG receptors). Increases in serum calcium were accompanied by elevated expression of intestinal calcium absorption genes (TRPV6, calbindin-9k).
  
  
  CONCLUSIONS
  Soy increases the bioavailability of endogenous and administered calcitriol, thereby enhancing its anticancer effects and risk of hypercalcemia. Since both agents are easily available as dietary supplements, the increased potential for hypercalcemic toxicity becomes an important factor when considering the combined use of vitamin D and soy in PCa therapy.
authors.affiliation: Division of Endocrinology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305-5103, USA.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Wang
authors.forename: Srilatha
authors.initials: S
authors.lastname: Swami
authors.forename: Aruna V
authors.initials: AV
authors.lastname: Krishnan
authors.forename: David
authors.initials: D
authors.lastname: Feldman
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002117:Calcitriol / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D019587:Dietary Supplements; D004359:Drug Therapy, Combination; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006934:Hypercalcemia / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011453:Prostaglandins / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D030262:Soybean Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D014815:Vitamins / Q000009:adverse effects / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011453:Prostaglandins; D030262:Soybean Proteins; D014815:Vitamins; D002117:Calcitriol