Retinoids in combination therapies for the treatment of cancer: mechanisms and perspectives
Introduction
Retinoids are derivatives of Vitamin A (retinol), which is essential for fertility and vision and plays a critical role in important biological functions including cell growth and differentiation, development, metabolism, and immunity. All-trans-retinoic acid (atRA) and 9-cis-RA are the active metabolites that regulate expression of target genes through binding to and activation of the nuclear retinoid receptors: atRA receptors (RARs) and Retinoid X receptors (RXRs). Retinoids inhibit the proliferation of cancer cells and induce cell differentiation of malignant cells, making these compounds one of the most prominent groups of chemopreventive agents.
Retinoid use in cancer therapy has been extensively studied over the years and almost certainly the best example is represented by the successful use of atRA in the treatment of acute promyelocytic leukemia (APL), while 13-cis-RA is effective against juvenile chronic myelogenous leukemia and mycosis fungoides (cutaneous T-cell lymphoma) in clinical studies. The combination of 13-cis-RA with interferon-α-2a (IFNα) has been shown to be effective against squamous cell carcinomas of skin and cervix. However, natural retinoids have shown limited efficacy in most solid malignancies. Furthermore, the reversible effect of retinoids requires prolonged treatments that are often associated with toxicity and the development of retinoid resistance. Although many of the factors influencing resistance are not well understood, aberrant expression and function of the retinoid-binding proteins or the nuclear retinoid receptors, as well as defects in retinoid metabolism, may result in sub-optimal clinical results. Most classical retinoids are also teratogenic and cause birth defects, raising major concerns for pregnant women. Because of the limited clinical efficacy, large efforts have been devoted during the last two decades to the synthesis of retinoid derivatives with selective activities, in an attempt to improve anticancer activity and to separate beneficial from toxic effects.
A major breakthrough in retinoid research was the isolation of the nuclear retinoid receptors and the elucidation of the mechanism of retinoid action. This allowed the identification of retinoids that selectively activate a subset of receptors and elicit a restricted biological response. Novel selective retinoids have become very promising as anticancer agents, either alone or in combination therapies. Indeed, some of these synthetic compounds or retinoid-related molecules (RRMs), which are selective for RARγ or inhibit receptor-mediated transcriptional activity (antagonists), have recently been shown to be potent inducers of apoptosis in cancer cells in vitro and to be effective against the growth of solid tumors in animal models with no overt signs of toxicity (Lu et al., 1997; Fanjul et al., 1998). A large body of literature has been produced over the years on clinical and preclinical studies using natural retinoids and related compounds (classical retinoids) alone or in combination therapies for the prevention and treatment of cancer. Many of the studies have recently been reviewed (Lotan and Hong, 2001; Nason-Burchenal and Dmitrovsky, 1999; Smith et al., 1992). We will focus on the most recent studies describing the use of retinoids in combination therapies for the treatment of cancer and the mechanism of apoptosis induction by novel selective RRMs with potential clinical applications, including a brief description of the mechanism of action of the nuclear retinoid receptors and selective retinoids.
Section snippets
Nuclear retinoid receptors mediate retinoid signals: the search for selective retinoids
Retinoid signals are mediated by the nuclear retinoid receptors, which belong to the nuclear hormone receptor superfamily of transcription factors. This includes receptors for steroid hormones, RA, thyroid hormone and Vitamin D3 (Piedrafita and Pfahl, 1999). In addition, a fast-growing group of orphan receptors has been described and a subset of these were found to respond to a variety of ligands (reviewed in the reference (Chawla et al., 2001)). The six known retinoid receptors (RARα, -β, -γ
Recent progress using retinoids in combination therapies: in vitro studies
Numerous studies in vitro and in animal models have demonstrated a synergistic action of retinoids in combination with other chemotherapeutic agents. Perhaps the most extensively analyzed combination is that of retinoids with interferons, both in vitro and in clinical trials. Mixed results have been obtained, depending on the type of tumor and even on different cell lines of the same type of cancer. Most studies have utilized atRA or 13-cis-RA with IFNα and have shown positive results in vitro
Retinoids in combination therapies: clinical trials
Retinoids have been tested in numerous clinical trials for the prevention of cancer based on their ability to induce cell differentiation and inhibit tumor growth in animal models. Studies were initiated with atRA (tretinoin) and 13-cis-RA (isotretinoin) (Table 1) and more recently the RARγ-selective compound 4-HPR was used alone or in combination with tamoxifen to prevent development of mammary tumors. Another promising compound, LGD 1069, is also effective in the chemoprevention of breast
Induction of apoptosis by selective RRMs: a novel RAR-independent mechanism of retinoid action
Three types of selective retinoids that induce apoptosis in cancer cells are particularly interesting for clinical evaluation. 4-HPR, which is already being tested in clinical trials under the name of fenretinide shows significant activity as chemopreventive agent and was found to induce apoptosis in HL-60 cells independently of the retinoid receptors (Delia et al., 1993). Production of reactive oxygen species occurred concomitant to 4-HPR treatment and antioxidants inhibited 4-HPR-induced
Perspectives
Although some retinoids are effective in single therapies for the prevention and treatment of certain malignancies, including skin cancer, APL, CTCL, and oral leukoplakia, most solid tumors are untreatable with currently available retinoids. Retinoids in combination with a variety of commonly used therapeutic agents have shown synergistic activities against the growth of different types of cancer cell lines in vitro. Many of those combinations were also effective in animal models and showed
Acknowledgements
Work in our laboratory is supported by grants from the NIH and the California Cancer Research Program. Retinoids used in our studies were provided by Maxia Pharmaceuticals and Galderma Research Inc.
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