Mechanisms of the Anti-Cancer and Anti-Inflammatory Actions of Vitamin D

Abstract

Calcitriol, the hormonally active form of vitamin D, is being evaluated in clinical trials as an anti-cancer agent. Calcitriol exerts multiple anti-proliferative, pro-apoptotic, and pro-differentiating actions on various malignant cells and retards tumor growth in animal models of cancer. Calcitriol also exhibits several anti-inflammatory effects including suppression of prostaglandin (PG) action, inhibition of p38 stress kinase signaling, and the subsequent production of pro-inflammatory cytokines and inhibition of NF-κB signaling. Calcitriol also decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis in breast cancer, both by a direct transcriptional repression and indirectly by reducing PGs, which are major stimulators of aromatase transcription. Other important effects include the suppression of tumor angiogenesis, invasion, and metastasis. These calcitriol actions provide a basis for its potential use in cancer therapy and chemoprevention. We summarize the status of trials involving calcitriol and its analogs, used alone or in combination with known anti-cancer agents.

1α,25-Dihydroxyvitamin D3 Inhibits Esophageal Squamous Cell Carcinoma Progression by Reducing IL6 Signaling

“…Recent research studies indicate that vitamin D 3 has antiinflammatory actions that likely contribute to its beneficial effects in multiple cancers (14,33). Inflammatory mediators, such as COX-2 and cytokines, enhance tumorigenesis through the activation of multiple signaling pathways in tumor tissue (17,37).…”

“…S4B) confirmed the in vitro findings. The inhibition of p38 signaling is classically anti-inflammatory and has been hypothesized to contribute to some of the activities of vitamin D in cancer prevention (14). By protein analysis in vitro and in vivo, calcitriol treatment inhibits p38 phosphorylation in cells ( Fig.…”

“…The potential to inhibit inflammation is considered an important mechanism responsible for the antitumor activity of vitamin D3 (14). Therefore, we examined the relationship between calcitriol, inflammation, and tumor progression using a 4-NQOinduced esophageal tumor mouse model.…”

“…Calcitriol is also reported to exhibit anti-inflammatory and immune-regulating effects, including suppression of prostaglandin (PG) action and the production of proinflammatory cytokines such as IL6 (13,14). Accumulating evidence has indicated that inflammatory responses are important for cancer development (15,16).…”

Recent Candidate Molecular Markers: Vitamin D Signaling and Apoptosis Specific Regulator of p53 (ASPP) in Breast Cancer

“…1α 25(OH) 2 D 3 suppresses the expression of several genes which are involved in prostaglandin pathway. Several invitro and invivo studies on breast cancer and prostate cancer showed 1α 25(OH) 2 D 3 significantly decreases the expression of cyclooxygenase-2 (COX-2) and stimulates 15-PGDH levels (Krishnan & Feldman, 2011). However, several invivo studies showed the inverse correlation between VDR and both COX-2 and 15-Hydroxyprostaglandin Dehydrogenase (15-PGDH), as well as between PGE2 and 1α 25(OH) 2 D 3 levels suggests a possible link between VDR associated target genes and prostaglandin metabolism in breast cancer and ovarian cancer (Figure 3) (Thill et al, 2010a;2010b).…”