Amancio Carnero

Oxidation of anticancer Pt(II) complexes with monodentate phosphane ligands: towards stable but active Pt(IV) prodrugs

The synthesis, characterization and cytotoxicity studies of two novel platinum(IV) complexes, trans-PtCl4(dma)(PPh3), 1, and trans-PtCl4(ipa)(PPh3), 2, where dma is dimethylamine and ipa is isopropylamine, have been carried out. Both complexes contain aliphatic amines trans to phosphane ligands as a good alternative to take advantage of the phosphane group lipophilicity and the stability of platinum(IV) to obtain more effective drugs. Moreover, the complexes are stable in solution and such stability allowed their antitumoral action and DNA interaction to be checked and proved.

Levels of active tyrosine kinase receptor determine the tumor response to Zalypsis

BackgroundZalypsis® is a marine compound in phase II clinical trials for multiple myeloma, cervical and endometrial cancer, and Ewing’s sarcoma. However, the determinants of the response to Zalypsis are not well known. The identification of biomarkers for Zalypsis activity would also contribute to broaden the spectrum of tumors by selecting those patients more likely to respond to this therapy.MethodsUsing in vitro drug sensitivity data coupled with a set of molecular data from a panel of sarcoma cell lines, we developed molecular signatures that predict sensitivity to Zalypsis. We verified these results in culture and in vivo xenograft studies.ResultsZalypsis resistance was dependent on the expression levels of PDGFRα or constitutive phosphorylation of c-Kit, indicating that the activation of tyrosine kinase receptors (TKRs) may determine resistance to Zalypsis. To validate our observation, we measured the levels of total and active (phosphorylated) forms of the RTKs PDGFRα/β, c-Kit, and EGFR in a new panel of diverse solid tumor cell lines and found that the IC50 to the drug correlated with RTK activation in this new panel. We further tested our predictions about Zalypsis determinants for response in vivo in xenograft models. All cells lines expressing low levels of RTK signaling were sensitive to Zalypsis in vivo, whereas all cell lines except two with high levels of RTK signaling were resistant to the drug.ConclusionsRTK activation might provide important signals to overcome the cytotoxicity of Zalypsis and should be taken into consideration in current and future clinical trials.

Synthesis, Reactivity Studies and Cytotoxicity of Two Iodidoplatinum(II) Complexes. Does Photoactivation Work?

Trans platinum complexes have been the landmark in unconventional drugs prompting the development of innovative structures that might exhibit chemical and biological profiles different to cisplatin. Iodido complexes made a new turning point in the platinum drug design field since their cytotoxicity was reevaluated and reported. In this new study, we have synthesized and evaluated diodido complexes bearing aliphatic amines and pyridines in trans configuration. X-ray diffraction support the structural characterization. Their cytotoxicity has been evaluated in tumor cell lines such as SAOS-2, A375, T-47D and HCT116. Moreover, we report their solution behavior and reactivity with biological models. UVA irradiation induces an increase in their reactivity towards model nucleobase 5 ́-GMP in early stages, and promotes the release of the pyridine ligand (spectator ligand) at longer reaction times. Density Functional calculations have been performed and the results are compared with our previous studies with other iodido derivatives.

Senescence in Oncogenesis: From Molecular Mechanisms to Therapeutic Opportunities

Somatic non stem cells show a spontaneous decline in growth rate in continuous culture related to an increasing number of population doublings, eventually terminating in a quiescent but viable state now known as replicative senescence. These cells show clear and distinctive morphological, physiological and biochemical characteristics. Moreover, the senescent phenotype is associated with a typical gene-expression profile. Similar behaviour has since then been observed in a wide variety of normal cells, and it is now widely accepted that normal somatic cells have an intrinsically limited proliferative lifespan, even under ideal growth conditions. Cells displaying characteristics of senescent cells, however, can be also observed in response to other stimuli, such as oncogenic stress, DNA damage or cytotoxic drugs. These non-proliferative characteristics prompted the scientists to look for therapies that can induce the senescent phenotype in tumor cells as therapeutic approach.