Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation

Abstract: Gain of function (GOF) DNA binding domain (DBD) mutations of TP53 upregulate chromatin regulatory genes that promote genome-wide histone methylation and acetylation. Here, we therapeutically exploit the oncogenic GOF mechanisms of p53 codon 158 (Arg158) mutation, a DBD mutant found to be prevalent in lung carcinomas. Using high throughput compound screening and combination analyses, we uncover that acetylating mutp53R158G could render cancers susceptible to cisplatin-induced DNA stress. Acetylation of mutp53R158G alters DNA binding motifs and upregulates TRAIP, a RING domain-containing E3 ubiquitin ligase which dephosphorylates IĸB and impedes nuclear translocation of RelA (p65), thus repressing oncogenic nuclear factor kappa-B (NF-ĸB) signaling and inducing apoptosis. Given that this mechanism of cytotoxic vulnerability appears inapt in p53 wild-type (WT) or other hotspot GOF mutp53 cells, our work provides a therapeutic opportunity specific to Arg158-mutp53 tumors utilizing a regimen consisting of DNA-damaging agents and mutp53 acetylators, which is currently being pursued clinically

Application of High Throughput Technologies in the Development of Acute Myeloid Leukemia Therapy: Challenges and Progress

Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by extensive heterogeneity in genetics, response to therapy and long-term outcomes, making it a prototype example of development for personalized medicine. Given the accessibility to hematologic malignancy patient samples and recent advances in high-throughput technologies, large amounts of biological data that are clinically relevant for diagnosis, risk stratification and targeted drug development have been generated. Recent studies highlight the potential of implementing genomic-based and phenotypic-based screens in clinics to improve survival in patients with refractory AML. In this review, we will discuss successful applications as well as challenges of most up-to-date high-throughput technologies, including artificial intelligence (AI) approaches, in the development of personalized medicine for AML, and recent clinical studies for evaluating the utility of integrating genomics-guided and drug sensitivity testing-guided treatment approaches for AML patients

<span style="font-size:11.0pt;mso-bidi-font-size: 10.0pt;font-family:"Times New Roman";mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-GB;mso-fareast-language:EN-US;mso-bidi-language:AR-SA" lang="EN-GB">Anticancer activity of sclerotiorin, isolated from an endophytic fungus <i style="mso-bidi-font-style:normal">Cephalotheca faveolata</i> Yaguchi, Nishim. & Udagawa</span>

464-468<span style="font-size:11.0pt;mso-bidi-font-size: 10.0pt;font-family:" times="" new="" roman";mso-fareast-font-family:batang;mso-ansi-language:="" en;mso-fareast-language:ko;mso-bidi-language:ar-sa"="" lang="EN">Biodiversity provides critical support for drug discovery. A significant proportion of drugs are derived, directly or indirectly, from biological sources. Through high throughput screening (HTS) and bioassay-guided isolation, bioactive compound sclerotiorin has been isolated from an endophytic fungus Cephalotheca faveolata. Sclerotiorin was found to be potent anti-proliferative against different cancer cells. In this study sclerotiorin has been found to induce apoptosis in colon cancer (HCT-116) cells through the activation of BAX, and down-regulation of BCL-2, those further activated cleaved caspase-3 causing apoptosis of cancer cells. </span

Hepatoprotective efficacy of Hypnea muciformis ethanolic extract on CCl4 induced toxicity in rats

The ethanolic extract of Hypnea muciformis (red algae) was tested for hepatoprotective activity against experimentally induced liver damage by Carbon tetrachloride (CCl4) in male albino rats. The levels of serum enzymatic and biochemical parameters such as serum glutamate oxaloacetate transaminase (SGOT), Serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), lactate dehydrogenase, 5' nucleotidase, bilirubin, creatinine, urea, triglycerides, lipid peroxides and albumin were determined. The CCI4 induced lesions in the liver significant increased the levels of serum marker enzymes SGPT and SGOT, bilirubin, creatinine and decreased urea. The oral treatment with ethanolic extract of H. muciformis exhibited significant hepatoprotective activity by reducing the CCL4 caused changes in the biochemical parameters such as total protein, total bilirubin, total cholesterol, triglycerides, and urea. These parameters were restored towards the normal levels as shown by the enzymatic tests. In addition, H. muciformis significantly decreased the liver weight of CCl4 intoxicated rats. Apparently the H. muciformis extract interfered with the free radical formation, which resulted in hepatoprotective activity. Acute toxicity studies revealed that the LD50 value was more than 3 g/kg body weight. These results clearly indicated that this seaweed contained some active principles in its ethanolic extract which acted as an antidote against the hepatotoxicity induced by CCl4

Dual Behavior of Ammonium Acetate for the Synthesis of Diverse Symmetrical/Unsymmetrical Bis[1,3]oxazines Possessing Anticancer Activity

<div><p></p><p>A simple and efficient approach was developed to synthesize symmetrical/unsymmetrical bis[1,3]oxazines using ammonium acetate with controllable substitution patterns in a one-pot fashion. In a representative crystal structure, the [1,3]oxazine ring is in a distorted semichair conformation with C2-carbon and nitrogen atoms residing above and below the naphthalene plane, leading to strain in the ring that allows ring-opening polymerization to take place. A few of the derivatives were found to possess anticancer activity. This current modest protocol affords numerous advantages such as mild reaction condition, shorter reaction time, operational simplicity, and excellent yield.</p></div