ABSTRACT
We previously demonstrated that some N-biphenylanilides caused cell-cycle arrest at G2/M transition in breast cancer cells. Among them we choose three derivatives, namely PTA34, PTA73 and RS35 for experimentation in solid tumor cell lines, classical Hodgkin Lymphoma (cHL) cell lines and bona fide normal cell lines. Almost all tumor cells were sensitive to compounds in the nanomolar range whereas, they were not cytotoxic to normal ones. Interestingly the compounds caused a strong G2/M phase arrest in cHL cell lines, thus, here we investigated whether they affected the integrity of microtubules in such cells. We found that they induced a long prometaphase arrest, followed by induction of apoptosis which involved mitochondria. PTA73 and RS35 induced the mitotic arrest through the fragmentation of microtubules which prevented the kinethocore-mitotic spindle interaction and the exit from mitosis. PTA34 is instead a tubulin-targeting agent because it inhibited the tubulin polymerization as vinblastine. As such, PTA34 maintained the Cyclin B1-CDK1 regulatory complex activated during the G2/M arrest while inducing the inactivation of Bcl-2 through phosphorylation in Ser70, the degradation of Mcl-1 and a strong activation of BIML and BIMS proapoptotic isoforms. In addition PTA34 exerted an antiangiogenic effect by suppressing microvascular formation.
Subject(s)
Antimitotic Agents/chemical synthesis , Biphenyl Compounds/chemical synthesis , Hodgkin Disease/metabolism , Nicotine/chemistry , Antimitotic Agents/chemistry , Antimitotic Agents/pharmacology , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , CDC2 Protein Kinase/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cyclin B1/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Hodgkin Disease/drug therapy , Humans , Membrane Potential, Mitochondrial/drug effects , Mitochondria/drug effects , Mitochondria/metabolism , Molecular Structure , Prometaphase/drug effectsABSTRACT
Several rhodium(I) and iridium(I) complexes displayed different degrees of antitumour activity when tested in mice bearing Ehrlich ascites carcinoma. Rhodium (I) and iridium (I) acetylacetonate derivatives caused a high percentage of cures. The rhodium (I) dimers were particularly interesting, since (bis(cycloocta-1,5-diene)micromicron' dichlorodirhodium(I) [RhCODCl]2) was highly effective, whereas its analogues, bis(bicyclo[2,2,1]hepta-2,5-diene)micromicron'-dichlorodirhodium(I) [RhNBDCl]2) and bis(1,5-hexadiene)micromicron' dichlorodirhodium(I) [RhEDCl]2) were virtually inactive. The absence of significant inhibition of DNA, RNA and protein syntheses in tumour cells found for [RhCODCl]2 at therapeutically active dosages, indicates that this substance has a different mechanism of action from that of cis-dichlorodiammine Pt(II) (cis-PDD). The amount of rhodium found in tumour cells after administration of active [RhCODCl]2 was higher than that for [RhEDCl]2, while the rhodium concentration in the ascitic fluid was much higher for [RhEDCl]2. A mechanism based on the chemical properties of the complexes is tentatively proposed for explaining these findings and selective toxicity for tumour cells.
