Retinoids as Differentiating Agents in Oncology: A Network of Interactions with Intracellular Pathways as the Basis for Rational Therapeutic Combinations

Abstract

Retinoic acid and natural as well as synthetic derivatives (retinoids) are promising anti-neoplastic agents endowed with both therapeutic and chemopreventive potential. Although the treatment of acute promyelocic leukemia with all-trans retinoic acid is an outstanding example, the full potential of retinoids in oncology has not yet been exploited and a more generalized use of these compounds is not yet a reality. This may be the result of issues such as natural and induced resistance as well as local and systemic toxicity. One way to enhance the therapeutic and chemopreventive activity of retinoic acid and derivatives is to identify rational combinations between these compounds and other pharmacological agents. This is now possible given the wealth of information available on the biochemical and molecular mechanisms underlying the biological activity of retinoids. At the cellular level, the anti-leukemia and anti-cancer activity of retinoids is the result of three main actions, cell-differentiation, growth inhibition and apoptosis. At the molecular level, retinoids act through the activation of nuclear-retinoic-acid-receptor-dependent and-independent pathways. The cellular pathways and molecular networks relevant for retinoid activity are modulated by a panoply of other intra-cellular and extra-cellular pathways that may be targeted by known drugs and other experimental therapeutics. The review article aims to summarize and critically discuss the available knowledge in the field and provide a rational framework that may be useful for the design of effective drug combinations with the potential to enhance the therapeutic index of retinoids.

Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA

“…All-trans retinoic acid (ATRA), the only clinically useful differentiating agent (Garattini et al, 2007) has potential for the therapy/chemoprevention of breast carcinoma (Decensi et al, 2000;Puntoni and Decensi, 2009). Given the heterogeneous nature of this tumor, a rational use of ATRA and derivatives (retinoids) in the clinic requires the identification of patients that would benefit from retinoid-based protocols.…”

Association of FABP5 Expression With Poor Survival in Triple-Negative Breast Cancer

“…Use of RA in cancer therapy, for example, is hampered by both the toxicity of RA and the development of resistance to RAmediated growth-inhibitory effects during tumorigenesis. 10 In fact, RA has been shown to stimulate the growth of a subset of breast cancers. 11,12 More recently, RA was found to inhibit proliferation of ER-positive human breast cancer cells, but had no effect on most ER-negative breast cancer cells.…”

Chemoprevention and Novel Treatments of Non-Muscle Invasive Bladder Cancer

“…Evidence suggests that it does this through a variety of molecular pathways including binding to nuclear retinoic acid receptors (RAR) and ligand activating transcription factors such as retinoid X receptors (RXR) (Simeone & Tari, 2004). Additionally, vitamin A's anti-tumor activity may involve, among others, interactions with growth factors and cytokines, neoplastic stem cell pathways such as WNT, cAMP pathways, mitogen activated protein kinases (MAPKs), PI3K/AKT, cyclin-dependent kinases (CDKs), protein kinase C, and epigenetic modulation of gene expression (Garattini et al, 2007). Other studies indicate that some synthetic retinoids may even reduce VEGF expression, which is an important angiogenic factor in bladder cancer growth (Hameed & el-Metwally, 2008).…”