Stacking of lowest-energy structures of Fe ₂ B ₂₄ ⁻ and Co ₂ B ₂₄ ⁻ dimers.

Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome associated with tumors of the brain, heart, kidney, and lung. The TSC protein complex inhibits the mammalian or mechanistic target of rapamycin complex 1 (mTORC1). Inhibitors of mTORC1, including rapamycin, induce a cytostatic response in TSC tumors, resulting in temporary disease stabilization and prompt regrowth when treatment is stopped. The lack of TSC-specific cytotoxic therapies represents an important unmet clinical need. Using a high-throughput chemical screen in TSC2-deficient, patient-derived cells, we identified a series of molecules antagonized by rapamycin and therefore selective for cells with mTORC1 hyperactivity. In particular, the cell-permeable alkaloid chelerythrine induced reactive oxygen species (ROS) and depleted glutathione (GSH) selectively in TSC2-null cells based on metabolic profiling. N-acetylcysteine or GSH cotreatment protected TSC2-null cells from chelerythrine's effects, indicating that chelerythrine-induced cell death is ROS dependent. Induction of heme-oxygenase-1 (HMOX1/HO-1) with hemin also blocked chelerythrine-induced cell death. In vivo, chelerythrine inhibited the growth of TSC2-null xenograft tumors with no evidence of systemic toxicity with daily treatment over an extended period of time. This study reports the results of a bioactive compound screen and the identification of a potential lead candidate that acts via a novel oxidative stress–dependent mechanism to selectively induce necroptosis in TSC2-deficient tumors. Implications: This study demonstrates that TSC2-deficient tumor cells are hypersensitive to oxidative stress–dependent cell death, and provide critical proof of concept that TSC2-deficient cells can be therapeutically targeted without the use of a rapalog to induce a cell death response. Mol Cancer Res; 13(1); 50–62. ©2014 AACR.

The MO diagrams and orbital contributions of the HOMO and LUMO for the Cu₇Sc and Cu₇Y clusters.

MTORC1 is a central signaling node in controlling cell growth, proliferation, and metabolism that is aberrantly activated in cancers and certain cancer-associated genetic disorders, such as tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis. However, while mTORC1-inhibitory compounds (rapamycin and rapalogs) attracted interest as candidate therapeutics, clinical trials have not replicated the promising findings in preclinical models, perhaps because these compounds tend to limit cell proliferation without inducing cell death. In seeking to address this issue, we performed a high-throughput screen for small molecules that could heighten the cytotoxicity of mTORC1 inhibitors. Here we report the discovery that combining inhibitors of mTORC1 and glutamate cysteine ligase (GCLC) can selectively and efficiently trigger apoptosis in Tsc2-deficient cells but not wild-type cells. Mechanistic investigations revealed that coinhibition of mTORC1 and GCLC decreased the level of the intracellular thiol antioxidant glutathione (GSH), thereby increasing levels of reactive oxygen species, which we determined to mediate cell death in Tsc2-deficient cells. Our findings offer preclinical proof of concept for a strategy to selectively increase the cytotoxicity of mTORC1 inhibitors as a therapy to eradicate tumor cells marked by high mTORC1 signaling, based on cotargeting a GSH-controlled oxidative stress pathway. Cancer Res; 76(16); 4816–27. ©2016 AACR.

Here, by utilizing crystal structure analysis through the particle swarm optimization (CALYPSO) structural searching method with density functional theory (DFT), we investigate the systemic structures and electronic properties of Ca₂Mg_n (n = 1–15) clusters. Structural searches found that two Ca atoms prefer to occupy the external position of magnesium-doped systems at n = 2–14. Afterward, one Ca atom begins to move from the surface into the internal of the caged skeleton at n = 15. Calculations of the average binding energy, second-order difference of energies, and HOMO–LUMO gaps indicated that the pagoda construction Ca₂Mg₈ (as the magic cluster) has higher stability. In addition, the simulated IR and Raman spectra can provide theoretical guidance for future experimental and theoretical investigation. Last, further electronic properties were determined, including the charge transfer, density of states (DOS) and bonding characteristics. We hope that our work will provide theoretical and experimental guidance for developing magnesium-based nanomaterials in the future.