Non-small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite sig Show more
Non-small cell lung cancer (NSCLC) is one of the most prevalent and lethal types of cancers worldwide and its high incidence and mortality rates pose a significant public health challenge. Despite significant advances in targeted therapy and immunotherapy, the overall prognosis of patients with NSCLC remains poor. Hypoxia is a critical driving factor in tumor progression, influencing the biological behavior of tumor cells through complex molecular mechanisms. The present review systematically examined the role of the hypoxic microenvironment in NSCLC, demonstrating its crucial role in promoting tumor cell growth, invasion and metastasis. Additionally, it has been previously reported that the hypoxic microenvironment enhances tumor cell resistance by activating hypoxia-inducible factor and regulating exosome secretion. The hypoxic microenvironment also enables tumor cells to adapt to low oxygen and nutrient-deficient conditions by enhancing metabolic reprogramming, such as through upregulating glycolysis. Further studies have shown that the hypoxic microenvironment facilitates immune escape by modulating tumor-associated immune cells and suppressing the antitumor response of the immune system. Moreover, the hypoxic microenvironment increases tumor resistance to radiotherapy, chemotherapy and other types of targeted therapy through various pathways, significantly reducing the therapeutic efficacy of these treatments. Therefore, it could be suggested that early detection of cellular hypoxia and targeted therapy based on hypoxia may offer new therapeutic approaches for patients with NSCLC. The present review not only deepened the current understanding of the mechanisms of action and role of the hypoxic microenvironment in NSCLC but also provided a solid theoretical basis for the future development of precision treatments for patients with NSCLC. Show less
A series of new chelating bidentate (SS) alkylimidazole-2-thione-Ru(II)/Os(II) complexes (3ai, 3aii, 3aiii, 3bii/4aiiiShow more
A series of new chelating bidentate (SS) alkylimidazole-2-thione-Ru(II)/Os(II) complexes (3ai, 3aii, 3aiii, 3bii/4aiii, 4bi, 4bii), and the tridentate (SNS) pyridine-2,6-diylimidazole-2-thione-Ru(II)/Os(II) complexes (5bi, 5civ/6bi, 6ci, 6civ) in the forms [MII(cym)(L)Cl]PF6 and [MII(cym)(L)]PF6 (M = Ru or Os, cym = η6-p-cymene, and L = heterocyclic derivatives of thiourea) respectively, were successfully synthesized. Spectroscopic and analytical methods were used to characterize the complexes and their ligands. Solid-state single-crystal X-ray diffraction analyses revealed a "piano-stool" geometry around the Ru(II) or Os(II) centers in the respective complexes. The complexes were investigated for in vitro chemotherapeutic activities against human cervical carcinoma (HeLa) and the non-cancerous cell line (Hek293) using the MTT assay. The compounds 3aii, 5civ, 5bi, 4aiii, 6ci, 6civ, and the reference drug, 5-fluorouracil were found to be selective toward the tumor cells; the compounds 3ai, 3aiii, 3bii, 4bi, 4bii, and 6bi, which were found not to be selective between normal and tumor cell lines. The IC50 value of the tridentate half-sandwich complex 5bi (86 ± 9 μM) showed comparable anti-proliferative activity with the referenced commercial anti-cancer drug, 5-fluorouracil (87 ± 15 μM). The pincer (SNS) osmium complexes 6ci (36 ± 10 μM) and 6civ (40 ± 4 μM) were twice as effective as the reference drug 5-fluorouracil at the respective dose concentrations. However, the analogous pincer (SNS) ruthenium complex 5civ was ineffective and did not show anti-proliferative activity, even at a higher concentration of 147 ± 1 μM. These findings imply that the higher stability of the chelating (SS) and the pincer (SNS) ligand architectures in the complexes improves the biological (anti-proliferative) activity of the complexes by reducing the chance of ligand dissociation under physiological conditions. In general, the pincer (SNS) osmium complexes were found to be more cytotoxic than their ruthenium analogues, suggesting that the anti-proliferative activity of the imidazole-2-thione-Ru/Os complexes depends on the ligand's spatial coordination, the nature of the metal center, and the charge of the metal complex ions. Show less
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we re Show more
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides (CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo, and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known mechanisms by which the peptides act and how these have been exploited in rationally designed combination therapies. We additionally discuss lacunae in our knowledge about the peptides that merit further research. Finally, we suggest both short- and long-term directions for creating new generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating brain and other malignancies. Show less
Platinum-based anticancer drugs represented by cisplatin play important roles in the treatment of various solid tumors. However, their applications are largely compromised by drug resistance and side Show more
Platinum-based anticancer drugs represented by cisplatin play important roles in the treatment of various solid tumors. However, their applications are largely compromised by drug resistance and side effects. Much effort has been made to circumvent the drug resistance and general toxicity of these drugs. Among multifarious designs, monofunctional platinum(II) complexes with a general formula of [Pt(3A)Cl] + (A: Ammonia or amine) stand out as a class of “non-traditional” anticancer agents hopeful to overcome the defects of current platinum drugs. This review aims to summarize the development of monofunctional platinum(II) complexes in recent years. They are classified into four categories: fluorescent complexes, photoactive complexes, targeted complexes, and miscellaneous complexes. The intention behind the designs is either to visualize the cellular distribution, or to reduce the side effects, or to improve the tumor selectivity, or inhibit the cancer cells through non-DNA targets. The information provided by this review may inspire researchers to conceive more innovative complexes with potent efficacy to shake off the drawbacks of platinum anticancer drugs. Show less
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology Show more
Abstract Significance: Mitochondria are the energetic, metabolic, redox, and information signaling centers of the cell. Substrate pressure, mitochondrial network dynamics, and cristae morphology state are integrated by the protonmotive force Δ p or its potential component, Δ Ψ , which are attenuated by proton backflux into the matrix, termed uncoupling. The mitochondrial uncoupling proteins (UCP1–5) play an eminent role in the regulation of each of the mentioned aspects, being involved in numerous physiological events including redox signaling. Recent Advances: UCP2 structure, including purine nucleotide and fatty acid (FA) binding sites, strongly support the FA cycling mechanism: UCP2 expels FA anions, whereas uncoupling is achieved by the membrane backflux of protonated FA. Nascent FAs, cleaved by phospholipases, are preferential. The resulting Δ p dissipation decreases superoxide formation dependent on Δ p . UCP-mediated antioxidant protection and its impairment are expected to play a major role in cell physiology and pathology. Moreover, UCP2-mediated aspartate, oxaloacetate, and malate antiport with phosphate is expected to alter metabolism of cancer cells. Critical Issues: A wide range of UCP antioxidant effects and participations in redox signaling have been reported; however, mechanisms of UCP activation are still debated. Switching off/on the UCP2 protonophoretic function might serve as redox signaling either by employing/releasing the extra capacity of cell antioxidant systems or by directly increasing/decreasing mitochondrial superoxide sources. Rapid UCP2 degradation, FA levels, elevation of purine nucleotides, decreased Mg 2+ , or increased pyruvate accumulation may initiate UCP-mediated redox signaling. Future Directions: Issues such as UCP2 participation in glucose sensing, neuronal (synaptic) function, and immune cell activation should be elucidated. Antioxid. Redox Signal. 29, 667–714. Show less