CYP3A4 overexpression

Additionally, a synthesized analogue with one [Ru(TPA)]2+ fragment (TPA = tris(pyridin-2-ylmethyl)amine) and two Ir(III) centers, although resistant to photochemical release, showed strong inhibition of CYP3A4 both in purified form and in CYP3A4-overexpressing HepG2 cells, with nanomolar potency. These mixed Ru(II)-Ir(III) compounds can permeate cell membranes and inhibit CYP3A4, presenting a new class of bioactive compounds.

We successfully established two different culture systems to simulate the liver first-pass effect in vitro. Such systems easily allow to study drug effects simultaneously on liver and on target cancer cells. They are of great value in pre-clinical cancer research, pharmaceutical research and drug development.

Finally, experiments in PHH corroborated the genotoxic potency ranking, and revealed genotoxic effects even in the absence of detectable cytotoxicity. In conclusion, our findings strongly support the concept of grouping PAs into potency classes and help to pave the way for a broader acceptance of relative potency factors in risk assessment.

EAI045 and cetuximab combined induce tumor regression in mouse models of EGFR-mutant lung cancer...Our results show that blood-brain barrier ABCB1 can markedly limit EAI045 brain accumulation. Moreover, elacridar coadministration can effectively reverse this process.

The optimized protocol, covering cell seeding in 96-well plates and analysis of supernatant by radio thin-layer-chromatography for higher throughput, was transferred to the evaluation of three F-labeled celecoxib-derived cyclooxygenase-2 inhibitors (coxibs)...Comparison with human and murine liver microsome assays showed good agreement with the human metabolite profile obtained by the HepG2 cell lines. Therefore, CYP-overexpressing HepG2 cells provide a good complement for assessing the metabolic stability of radiotracers and allow the analysis of the CYP isoform-specific contribution to the overall radiotracer metabolism.

The obtained results may help to further optimize the safety and efficacy of sotorasib in clinical use. DATA AVAILABILITY STATEMENT: The data that supports the findings of this study are available in the supplementary material of this article.

Other cell functions, including ATP synthesis and consequently the proliferation were negatively affected in both in vitro cell models. Since neither cell integrity nor cell viability were reduced, the effect of DPI in HepG2 can be assessed as cytostatic rather than cytotoxic.