The roles of the hypothalamus and particularly the lateral hypothalamus (LH) in the regulation of inflammation and pain have been widely studied. The LH consists of a parasympathetic area that has connections with all the major parts of the brain. It controls the autonomic nervous system (ANS), regulates feeding behavior and wakeful cycles, and is a part of the reward system. In addition, it contains different types of neurons, most importantly the orexin neurons. These neurons, though few in number, perform critical functions such as inhibiting pain transmission and interfering with the reward system, feeding behavior and the hypothalamic pituitary axis (HPA). Recent evidence has identified a new role for orexin neurons in the modulation of pain transmission associated with several inflammatory diseases, including rheumatoid arthritis and ulcerative colitis. Here, we review recent findings on the various physiological functions of the LH with special emphasis on the orexin/receptor system and its role in mediating inflammatory pain.
Immunotherapy is an emerging form of cancer therapy that is associated with promising outcomes. However, most cancer patients either do not respond to immunotherapy or develop resistance to treatment. The resistance to immunotherapy is poorly understood compared to chemotherapy and radiotherapy. Since immunotherapy targets cells within the tumor microenvironment, understanding the behavior and interactions of different cells within that environment is essential to adequately understand both therapy options and therapy resistance. This review focuses on reviewing and analyzing the special features of cancer stem cells (CSCs), which we believe may contribute to cancer resistance to immunotherapy. The mechanisms are classified into three main categories: mechanisms related to surface markers which are differentially expressed on CSCs and help CSCs escape from immune surveillance and immune cells killing; mechanisms related to CSC-released cytokines which can recruit immune cells and tame hostile immune responses; and mechanisms related to CSC metabolites which modulate the activities of infiltrated immune cells in the tumor microenvironment. This review also discusses progress made in targeting CSCs with immunotherapy and the prospect of developing novel cancer therapies.
Polo-like kinase 1 (PLK1) is an essential protein kinase with multiple roles in mitotic progression. PLK1 consists of a kinase domain (KD) and a phosphopeptide-binding polobox domain (PBD), which is responsible for substrate recognition and subcellular localization. The regulation of PLK1 involves an autoinhibitory conformation in which KD and PBD interact. Our previous work identified PBD-binding molecules termed abbapolins that inhibit the cellular phosphorylation of a PLK1 substrate and induce the loss of intracellular PLK1.Here, we describe a comparison of the abbapolin activity with that of KD inhibitors to gain insight into conformational features of PLK1. As measured by a cellular thermal shift assay, abbapolins produce ligand-induced thermal stabilization of PLK1. In contrast, KD inhibitors decreased the soluble PLK1, suggesting that catalytic-site binding causes a less thermally stable PLK1 conformation. Binding measurements with full-length PLK1 and a KD inhibitor also demonstrated a conformational change. Interestingly, the cellular consequences of KD versus PBD engagement contrast as KD binding causes the accumulation of intracellular PLK1, whereas PBD binding produces a striking loss of nuclear PLK1. These data are consistent with the relief of autoinhibited PLK1 by KD binders; an explanation for these observations is presented using structures for the catalytic domain and full-length PLK1 predicted by AlphaFold. Collectively, the results highlight an underappreciated aspect of targeting PLK1, namely, conformational perturbations induced by KD versus PBD binding. In addition to their significance for PBD-binding ligands, these observations have implications for the development of ATP-competitive PLK1 inhibitors because catalytic inhibitors may conversely promote PLK1 noncatalytic functions, which may explain their lack of clinical efficacy to date.
Polo-like kinase 1 (PLK1) has a plethora of roles within the cell of which mitotic regulation is the best characterized. This kinase is overexpressed and upregulated in cancer cells, making it an attractive target for therapeutics. Drug discovery efforts have mainly focused on the ATP binding site however have met with little clinical success to date. Targeting substrate recognition and subcellular localization through the Polo-Box domain represents an attractive alternative to generating PLK1 specific compounds and to avoid the tumor suppressor functions of PLK3. REplacement with Partial Ligand Alternatives through Computational Enrichment, REPLACE, is validated strategy used to convert peptide inhibitors of protein-protein interactions into more drug like compounds. Through the use of this methodology, we have discovered promising non-ATP competitive inhibitors based on a 2-(4-AlkylBenzamido) Benzoic Acid (ABBA) pharmacophore which bind to the polo-box domain of PLK1. These compounds, designated as abbapolins, engage PLK1 as evidenced by their ability to block phosphorylation of TCTP, a key substrate of PLK1, induce PLK1 degradation and are potently anti-proliferative in prostate cancer cell lines. Based on these observations, lead compounds were investigated further for their pharmacokinetic properties and in vivo efficacy and key compounds showed development potential based upon preliminary results. To further investigate their potential in other tumors, selected abbapolins were tested against the NCI-60 tumor cell panel and other cancers with poor prognosis. Results indicate that neuroblastoma, lung, colorectal and certain leukemias are the most sensitive cell lines and thus provide impetus to investigate the abbapolins for difficult to treat and resistant tumors. We present the further optimization of the abbapolins to determine their structure-activity relationship and identify compounds with novel structures and improved drug-like properties. This includes their ability to engage PLK1 and anti-proliferative activities against selected cell lines that represent therapeutically challenging cancers. Furthermore, these compounds serve as chemical biology probes to elucidate roles of the PBD in conformationally regulating PLK1 activity, through in vitro experiments and specifically in the abbapolin sensitive cell lines. Citation Format: Jessy Stafford, Danda Chapagai, George Merhej, Justin Pressley, Chintada Nageswara-Rao, Michael Wyatt, Campbell Mcinnes. Development of abbapolin inhibitors of the PLK1 PBD as potential therapeutics for prostate and other challenging cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4993.
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