BODIPY-Appended Pt(II) Complexes with High Toxicities and Anti-chemoresistance Performances in a Cisplatin Resistant In Vivo Model.

Two novel fluorophore (BODIPY)-bearing complexes, pyriplatin (mCBP) and pyrimidine-chelated cisplatin (dCBP), were synthesized and characterized. The additional BODIPY-pyridine/pyridimine motifs of the two Pt(II) complexes resulted in stronger interactions with DNA in comparison with those of cisplatin. mCBP and cisplatin caused relative decreases in life span and body length in a cisplatin resistant in vivo model, N2 (wild-type) Caenorhabditis elegans. In contrast, dCBP resulted in a dramatic reduction in the two physiological parameters in N2 C. elegans, indicating high toxicity and sensitivity. The resistance factors (RF) of cisplatin, mCBP, and dCBP were determined to be 2.46, 1.04, and 0.91, respectively. The increasing RF folds for mCBP and dCBP against cisplatin were 2.36 and 2.70, respectively. This suggested they were featured with improved anti-chemoresistance capabilities. It is noteworthy that dCBP showed lowest lethal concentration (LC50) values of 0.56 and 0.61 mM in cisplatin resistant and sensitive in vivo models, respectively. Upregulation of several evolutionary conservation genes that regulate cisplatin chemoresistance through cisplatin effluxing, the DNA damage response, the unfolded protein response, and detoxification (asna-1, parp-1, enpl-1, and skn-1) was observed upon exposure to cisplatin but not to mCBP and dCBP. This could explain the improved anti-chemoresistance performances of synthesized Pt(II) complexes.

Up-regulation of microtubule-associated protein 4 and drebrin A mRNA expression by antidepressants in rat hippocampus following chronic stress.

We used the differential display-polymerase chain reaction (DD-PCR) protocol to identify genes related to antidepressant effects. Rats were subjected to different kinds of stress for 20 days, and then the antidepressants desipramine and fluoxetine were administered (10 mg/kg per day, i.p.) for 20 days. DD-PCR was performed and differentially expressed cDNAs were further confirmed by dot-blot hybridization. cDNA homology analysis revealed that desipramine up-regulated the expression of microtubule-associated protein 4 (MAP-4) mRNA and fluoxetine up-regulated the expression of drebrin A mRNA in the rat hippocampus compared with the chronically stressed group. This result suggests that MAP-4 and drebrin may be involved in the antidepressant like effects of desipramine and fluoxetine.