In addition to its well-established effects on the regulation of calcium homeo-stasis, 1a,25-(OH)2D3has potent regulatory effects on cell growth and differentiation. Experimental evidence suggests a role for 1a,25-(OH)2D3 in tumor cell killing, anti-angiogenesis, and interference with tumor cell invasion, thus making it a potential candidate agent for cancer regulation. 1a,25-(OH)2D3 has been recognized for its regulatory effects on cell cycle checkpoints in several cell types. It has a major inhibitory effect on the Gj-S progression by upregulating the cyclin-dependent kinase inhibitors p21 and p27 along with the inhibition of cyclin D1.66 1a,25-(OH)2D3 indirectly regulates the cell cycle by increasing the expression of transforming growth factor-beta (TGF-P)6768 and decreasing that of epidermal growth factor receptor (EGFR).69-72 The pro-apoptotic effects observed with vitamin D3 are believed to be mediated either indirectly through insulin-like growth receptor and tumor necrosis factor-a or more directly through BCL-2 family proteins, ceramide pathways, death receptors such as fas, and stress-activated protein kinases (JNK, MAPK, and p38).667374 Studies demonstrate that 1a,25-(OH)2D3 is capable of inhibiting tumor cell invasion, metastasis, and angio-genesis via mechanisms that may include regulation of serine proteinases and metalloproteinases.66
Despite the overwhelming evidence that 1a,25-(OH)2D3 is not just a nutrient but may be involved in a wide range of activities, its hypercalcemic actions have hindered its potential as a clinically useful anticancer agent. To overcome this effect, several groups have developed analogs of 1a,25-(OH)2D3 in an attempt to dissociate its antiproliferative activity from its calcemia-inducing activity. To this date there are at least 2000 1a,25-(OH)2D3 analogs, now called deltanoids, that are available for research purpose with a considerable number of analogs at the preclinical/clinical stage of evaluation.
There is extensive literature available on the use of deltanoids as anticancer agents. With VDR being expressed in more than 30 nonclassical target tissues and many cancer-related cells, the deltanoids have been shown to inhibit cell proliferation in many tumor cell types in culture. Initial findings using hemato-poietic-derived tumor cells showed inhibition of cell proliferation. Further evidence indicated the versatile use of deltanoids across several nonhematopoietic malignancies including transformed breast, prostate, skin, lung, colon, ovary, pancreas cells, as well as neuroblastoma and melanoma cells.6675-7980 Although much of the mechanistic data gathered in vitro point toward cell cycle arrest, differentiation, and induction of apoptosis, the proposed mechanism of action of deltanoids is likely to differ based on the type of tumor model examined. No unified hypothesis has emerged so far on the basis for the anticancer effects of 1a,25-(OH)2D3and its analogs. In addition, as supraphysiological concentrations are often required to achieve anticancer effects when used alone, recent reports suggest that deltanoids could be more valuable when used in conjunction with other anticancer treatments.
In 1997, Light et al.81 reported that treatment of murine squamous carcinoma cells with 1a,25-(OH)2D3 or its analog Ro23-7553 resulted in a significant growth inhibition, with accumulation of cells in G0-Gj and an accompanying decrease of cells in S phase. The ability to arrest cells in G0-Gj was exploited by combining Ro23-7553 with the cytotoxic agent cisplatin (cis-diamminodichloroplatinum; cDDP). Pretreatment with deltanoids for 24 to 48 h significantly enhanced cDDP-mediated tumor cell kill as compared to concurrent treatment with Ro23-7553 and cDDP or cDDP alone.
Deltanoids can be effectively combined with ionizing radiation and chemo-therapeutic agents such as adriamycin to induce apoptosis in breast tumor models both in vitro and in vivo.82-86 While the primary response of breast tumor cells to deltanoids such as EB 1089 is growth inhibition, apoptosis has been observed in a fraction of the cell population. The possibility that the combination of deltanoids with radiation might promote cell death (i.e., through a differentiation stimulus plus DNA damage) was investigated by exposing both TP53 wild-type and TP53-mutated breast tumor cells to 1a,25-(OH)2D3 or EB 1089 for 48 h prior to irradiation. The combination of deltanoids with radiation resulted in enhanced antiproliferative effects in the TP53 wild-type MCF-7 cells based on both a clonogenic assay and the determination of numbers of viable cells. The combination of EB 1089 with radiation increased DNA fragmentation based on both the terminal transferase end-labeling (TUNEL) and bisbenzamide spectrofluoro-metric assays, suggesting the promotion of apoptosis. Enhancement of local tumor control by deltanoids followed with fractionated radiation was further substantiated in vivo with the use of EB 1089, partly through the promotion of apoptotic cell death.
Treatment with EB 1089 was found to block the increase in p21waf1/cip1 levels induced by adriamycin and interfere with induction of MAP kinase activity by ionizing radiation. These effects may be related to the capacity of EB 1089 to promote secretion of insulin-like growth factor binding protein. Similarly, pretreatment with another deltanoid, ILX 23-7553, shifted the dose-response curve for clonogenic survival, increasing sensitivity to adriamycin 2.5-fold and sensitivity to radiation fourfold. Our recent studies demonstrate that EB 1089 delays the accelerated senescence response to fractionated ionizing radiation in the breast tumor cells, promotes cell death in the irradiated cells, and delays proliferative recovery.8287 Taken together these findings indicate that deltanoids sensitize breast tumor cells to certain anticancer treatments. These data support the concept that deltanoids could have utility in combination with conventional chemotherapy or radiotherapy in the treatment of cancer.
Trump and Johnson's research groups88-92 have conducted several studies both in vitro and in vivo on the various combinations of 1a,25-(OH)2D3 and other antitumor agents. Yu et al.93 have shown that 1a,25-(OH)2D3 increased mito-xantrone/dexamethasone-mediated growth inhibition in prostate cancer PC-3 cells (p < 0.05) and that 1a,25-(OH)2D3 acted synergistically with mitoxantrone. Additionally, such a combination was shown to reduce the surviving fraction per gram tumor compared with mitoxantrone/dexamethasone or untreated controls (p < 0.03). The authors have further demonstrated the use of such combination therapy in other tumor models including murine squamous cell carcinoma (SCCVII/SF).81,91-93 The growth of SCCVII/SF tumors was inhibited in mice treated simultaneously with dexamethasone and 1a,25-(OH)2D3 when compared to no treatment or single-agent treatment. In this case total VDR content in SCCVII/SF cells was increased after treatment with dexamethasone. Treatment of tumor-bearing animals with dexamethasone (9 ^g/day) for 7 days also led to increased VDR-ligand-binding activities in whole-cell extracts from tumor or kidneys and decreased activity in intestinal mucosa. It therefore appears that dexamethasone is capable of enhancing the antitumor effect of 1a,25-(OH)2D3 by regulating VDR-ligand-binding activity.
The strategy of combining deltanoids with multiple anti-cancer agents is promising. Danilenko and Studzinski94 have summarized an extensive range of compounds and agents that have been used in combination with deltanoids to increase their differentiation-inducing and antiproliferative activities. They have also discussed in detail the possible mechanistic basis for the observed synergy or additive effect of deltanoids in several different tumor types. Evidence available from the literature on the potentiation of deltanoid effects with other differentiation agents, plant derived compounds, antioxidants, and other agents is presented in the review article by Danilenko and Studzinski.94
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