ent-Kauranes are diterpene-type compounds commonly found in most plant species, especially from the Euphorbiaceae family. These compounds have been studied due to their anti-inflammatory and anti-tumor properties. Regulation of apoptosis, or programmed cell death, is commonly bypassed by tumoral cells, giving rise to uncontrolled proliferating cells, which eventually become carcinogenic. In a previous work, we showed that both mRNA and protein expression levels of the antiapoptotic gene Bcl-2 are reduced in MCF-7 cancer cells by the effect of the natural diterpene ent-16β-17α-dihydroxykaurane (DHK). This effect was not directly associated with the inactivation of NF-κB, as has been shown with other diterpenes compounds. Herein, we report that DHK is dissociating the Ap2α-Rb activating complex, affecting its binding ability for the Bcl-2 gene promoter. These events down-regulate Bcl-2 and is temporally accompanied by the induction of E2F1 and its target pro-apoptotic gene Puma. Disruption of the Rb-Ap2α activation complex was corroborated by chromatin immunoprecipitation and protein immunolocalization, which also revealed that Ap2α sorts out from the nucleus and relocalizes in the cell periphery. Taken together, our study confirms the regulation of Bcl-2 gene transcription by the Ap2α-Rb complex and describes a singular protein relocalization for Ap2α induced by DHK, implicating a new potential therapeutic target to differentially onset apoptosis in tumor cells.

13,14-Dihydroxy-8,11,13-podocarpatrien-7-one (1) and a series of ring C aromatic diterpene derivatives were synthesised from (+)-manool (4) and evaluated for their cytotoxic, leishmanicidal and trypanocidal activities. Our results indicated that compound 1 and other podocarpane-type intermediates are cytotoxic. Cleavage of C6-C7 bond of compound 7 improved cytotoxic activity, indicating that, in particular, the 6,7-seco-podocarpane-type compound 20 might serve as a lead compound for further development.

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