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Carnosic Acid Potentiates the Antioxidant and Prodifferentiation Effects of 1,25-Dihydroxyvitamin D₃ in Leukemia Cells but Does Not Promote Elevation of Basal Levels of Intracellular Calcium¹

Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel [M. D., J. L., Y. S.], and Department of Pathology and Laboratory Medicine, UMD–New Jersey Medical School, Newark, New Jersey 07103 [Q. W., X. W., G. P. S.]

Differentiation therapy of cancer remains an only partially attained goal. Agents currently under active investigation include derivatives of vitamin D, modeled on its physiological hormone form, 1,25-dihydroxyvitamin D₃ (1,25D₃), but the calcemic effects of these compounds preclude their use in the clinic. An approach that may obviate this problem is to combine 1,25D₃ or its derivatives with other agents that increase the antineoplastic effects of low, nontoxic concentrations of vitamin D compounds. We have recently used the plant-derived polyphenolic antioxidant, carnosic acid (CA), to demonstrate an increase in the differentiating action of 1,25D₃ on human leukemia cells under these conditions (M. Danilenko et al., JNCI, 93: 1224–1233, 2001). We now show that treatment of HL60-G cells with either CA or 1,25D₃ alone resulted in a decrease in the intracellular levels of reactive oxygen species. Furthermore, the combination of 10 µM CA and a low concentration of 1,25D₃ (1 nM) produced an enhanced antioxidant effect, which correlated with the potentiation of monocytic differentiation. Other plant antioxidants tested (curcumin, silibinin, and the organoselenium antioxidant ebselen) also potentiated differentiation induced by 1,25D₃, although alone, they had only minor differentiating effects. Differentiation induced by CA/1,25D₃ combinations was associated with increased intracellular glutathione content, whereas buthionine sulfoxime decreased both differentiation and the cellular glutathione content. This combination also enhanced the activation of the Raf-mitogen-activated protein/extracellular signal-regulated kinase kinase-extracellular signal-regulated kinase mitogen-activated protein kinase module and increased the binding of the activator protein-1 (AP-1) transcription factor to its cognate DNA element in the promoter regions of vitamin D receptor gene, suggesting that the mechanism of potentiation is at least in part attributable to induction and activation of components of this mitogen-activated protein kinase pathway. Cell treatment with a high concentration of 1,25D₃ (100 nM) resulted in a substantial elevation of basal intracellular calcium concentration. In contrast, importantly for an eventual clinical application of these studies, the potentiating action of CA on differentiation induced by a low concentration of 1,25D₃ (1 nM) was not accompanied by an elevation of basal intracellular calcium concentration. These findings suggest that combinations of CA with derivatives of vitamin D should be evaluated for use in differentiation therapy of myeloid leukemias.

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