Bak and Bcl-xL Participate in Regulating Sensitivity of Solid Tumor Derived Cell Lines to Mcl-1 Inhibitors.

BH3 mimetics represent a promising tool in cancer treatment. Recently, the drugs targeting the Mcl-1 protein progressed into clinical trials, and numerous studies are focused on the investigation of their activity in various preclinical models. We investigated two BH3 mimetics to Mcl-1, A1210477 and S63845, and found their different efficacies in on-target doses, despite the fact that both agents interacted with the target. Thus, S63845 induced apoptosis more effectively through a Bak-dependent mechanism. There was an increase in the level of Bcl-xL protein in cells with acquired resistance to Mcl-1 inhibition. Cell lines sensitive to S63845 demonstrated low expression of Bcl-xL. Tumor tissues from patients with lung adenocarcinoma were characterized by decreased Bcl-xL and increased Bak levels of both mRNA and proteins. Concomitant inhibition of Bcl-xL and Mcl-1 demonstrated dramatic cytotoxicity in six of seven studied cell lines. We proposed that co-targeting Bcl-xL and Mcl-1 might lead to a release of Bak, which cannot be neutralized by other anti-apoptotic proteins. Surprisingly, in Bak-knockout cells, inhibition of Mcl-1 and Bcl-xL still resulted in pronounced cell death, arguing against a sole role of Bak in the studied phenomenon. We demonstrate that Bak and Bcl-xL are co-factors for, respectively, sensitivity and resistance to Mcl-1 inhibition.

Neurohybrid Memristive CMOS-Integrated Systems for Biosensors and Neuroprosthetics.

Here we provide a perspective concept of neurohybrid memristive chip based on the combination of living neural networks cultivated in microfluidic/microelectrode system, metal-oxide memristive devices or arrays integrated with mixed-signal CMOS layer to control the analog memristive circuits, process the decoded information, and arrange a feedback stimulation of biological culture as parts of a bidirectional neurointerface. Our main focus is on the state-of-the-art approaches for cultivation and spatial ordering of the network of dissociated hippocampal neuron cells, fabrication of a large-scale cross-bar array of memristive devices tailored using device engineering, resistive state programming, or non-linear dynamics, as well as hardware implementation of spiking neural networks (SNNs) based on the arrays of memristive devices and integrated CMOS electronics. The concept represents an example of a brain-on-chip system belonging to a more general class of memristive neurohybrid systems for a new-generation robotics, artificial intelligence, and personalized medicine, discussed in the framework of the proposed roadmap for the next decade period.