Page 67 - Vitamin D and Cancer

54 A.V. Krishnan and D. Feldman

Keywords Calcitriol • Prostate cancer • Breast cancer • Colorectal cancer
• Anti-inflammatory actions • Prostaglandins • IGFBP-3 • MKP5 • Inflammatory
cytokines • NFkB • Chemoprevention and treatment

3.1 Introduction

Calcitriol (1,25-dihydroxyvitamin D ), the biologically most active form of vitamin
3
D, exerts antiproliferative and pro-differentiating effects in a number of malignant
cells raising the possibility of its use as an anticancer agent as described in many
chapters of this volume. In vivo studies have also demonstrated an anticancer effect
of calcitriol to retard the development and growth of tumors in animal models.
Many molecular pathways mediate the anticancer effects of calcitriol [1]. Recent
research, including observations from our laboratory, suggests that calcitriol exhib-
its anti-inflammatory actions that may contribute to its beneficial effects in several
cancers, in addition to the other actions described in this book. Inflammation has
been suggested to contribute to the development and progression of many cancers
[2] including prostate [3], breast [4], colon [5], lung [6], ovarian [7], liver [8], and
skin [9] cancers. Inflammatory mediators enhance tumorigenesis through the acti-
vation of multiple signaling pathways. Our observations in prostate cancer (PCa)
cells reveal that calcitriol exerts important regulatory effects on some of the key
molecular pathways involved in inflammation. In this chapter, we will discuss the
role of the anti-inflammatory actions of calcitriol and its potential chemopreventive
and therapeutic utility in cancer.

3.2 Inflammation and Cancer

Chronic inflammation has been recognized as a risk factor for cancer development
[10, 11]. Inflammation can be triggered by a variety of stimuli such as injury or
infection, autoimmune disease, the development of benign or malignant tumors, or
other pathologies. The responses of the immune system in fighting the development
of tumors may also fuel the process of tumorigenesis. Cancer-related inflammation
is characterized by the presence of inflammatory cells at the tumor sites and the
overexpression of inflammatory mediators such as cytokines, chemokines, prosta-
glandins (PGs), and reactive oxygen and nitrogen species in tumor tissue [10–13].
Many of these pro-inflammatory mediators activate angiogenic switches usually
under the control of vascular endothelial growth factor (VGEF) and thereby promote
tumor angiogenesis, metastasis, and invasion [2, 14]. Epidemiological studies show
a decrease in the risk of developing several cancers associated with the intake of
antioxidants and non-steroidal anti-inflammatory drugs (NSAIDs) [14–16]. Current
research has begun to unravel several molecular pathways that link inflammation
and cancer. Our observations in PCa as well as those of others in several cancers