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Biochimica Et Biophysica Acta. Reviews... Jul 2024Apoptosis has traditionally been regarded as the desired cell death pathway activated by chemotherapeutic drugs due to its controlled and non-inflammatory nature.... (Review)
Review
Apoptosis has traditionally been regarded as the desired cell death pathway activated by chemotherapeutic drugs due to its controlled and non-inflammatory nature. However, recent discoveries of alternative cell death pathways have paved the way for immune-stimulatory treatment approaches in cancer. Ferroptosis (dependent on iron) and cuproptosis (dependent on copper) hold promise for selective cancer cell targeting and overcoming drug resistance. Copper ionophores and iron-bearing nano-drugs show potential for clinical therapy as single agents and as adjuvant treatments. Here we review up-to-date evidence for the involvement of metal ion-dependent cell death pathways in the cytotoxicity of classical chemotherapeutic agents (alkylating agents, topoisomerase inhibitors, antimetabolites, and mitotic spindle inhibitors) and their combinations with cuproptosis and ferroptosis inducers, indicating the prospects, advantages, and obstacles of their use.
Topics: Ferroptosis; Humans; Neoplasms; Copper; Antineoplastic Agents; Iron; Animals; Signal Transduction; Cell Death
PubMed: 38801962
DOI: 10.1016/j.bbcan.2024.189124 -
Journal of Medicinal Chemistry Dec 2023Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of...
Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties. This led to the discovery of the potent, selective, orally bioavailable CDK9 inhibitor (). Compound exhibits antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.
Topics: Adult; Humans; Animals; Mice; Cyclin-Dependent Kinases; Cell Line, Tumor; Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Disease Models, Animal; Protein Kinase Inhibitors; Cyclin-Dependent Kinase 9; Neoplasms
PubMed: 37967851
DOI: 10.1021/acs.jmedchem.3c01233 -
Cancer Gene Therapy Aug 2023Despite the development of new classes of targeted anti-cancer drugs, the curative treatment of metastatic solid tumors remains out of reach owing to the development of... (Review)
Review
Despite the development of new classes of targeted anti-cancer drugs, the curative treatment of metastatic solid tumors remains out of reach owing to the development of resistance to current chemotherapeutics. Although many mechanisms of drug resistance have been described, there is still a general lack of understanding of the many means by which cancer cells elude otherwise effective chemotherapy. The traditional strategy of isolating resistant clones in vitro, defining their mechanism of resistance, and testing to see whether these mechanisms play a role in clinical drug resistance is time-consuming and in many cases falls short of providing clinically relevant information. In this review, we summarize the use of CRISPR technology, including the promise and pitfalls, to generate libraries of cancer cells carrying sgRNAs that define novel mechanisms of resistance. The existing strategies using CRISPR knockout, activation, and inhibition screens, and combinations of these approaches are described. In addition, specialized approaches to identify more than one gene that may be contributing to resistance, as occurs in synthetic lethality, are described. Although these CRISPR-based approaches to cataloguing drug resistance genes in cancer cells are just beginning to be utilized, appropriately used they promise to accelerate understanding of drug resistance in cancer.
Topics: Humans; RNA, Guide, CRISPR-Cas Systems; Antineoplastic Agents; Neoplasms; CRISPR-Cas Systems
PubMed: 37029320
DOI: 10.1038/s41417-023-00608-z -
Aging Nov 2023
Topics: Humans; Artificial Intelligence; Geroscience; Neoplasms; Antineoplastic Agents; Drug Development
PubMed: 37980599
DOI: 10.18632/aging.204914 -
International Journal of Molecular... May 2024When, in 2022, the asked me to edit the Special Issue, I was quick to propose the title 'Novel Chemical Tools for Targeted Cancer Therapy' [...].
When, in 2022, the asked me to edit the Special Issue, I was quick to propose the title 'Novel Chemical Tools for Targeted Cancer Therapy' [...].
Topics: Humans; Neoplasms; Molecular Targeted Therapy; Antineoplastic Agents
PubMed: 38892232
DOI: 10.3390/ijms25116044 -
Aging Apr 2024Ubiquitination of the proteins is crucial for governing protein degradation and regulating fundamental cellular processes. Deubiquitinases (DUBs) have emerged as... (Review)
Review
Ubiquitination of the proteins is crucial for governing protein degradation and regulating fundamental cellular processes. Deubiquitinases (DUBs) have emerged as significant regulators of multiple pathways associated with cancer and other diseases, owing to their capacity to remove ubiquitin from target substrates and modulate signaling. Consequently, they represent potential therapeutic targets for cancer and other life-threatening conditions. USP43 belongs to the DUBs family involved in cancer development and progression. This review aims to provide a comprehensive overview of the existing scientific evidence implicating USP43 in cancer development. Additionally, it will investigate potential small-molecule inhibitors that target DUBs that may have the capability to function as anti-cancer medicines.
Topics: Humans; Neoplasms; Animals; Ubiquitination; Endopeptidases; Deubiquitinating Enzymes; Signal Transduction; Antineoplastic Agents
PubMed: 38613804
DOI: 10.18632/aging.205731 -
Biomedicine & Pharmacotherapy =... Jan 2024Hepatocellular carcinoma (HCC) remains a major global health burden, and sorafenib, a multi-kinase inhibitor, has shown effectiveness in the treatment of HCC and is... (Review)
Review
Hepatocellular carcinoma (HCC) remains a major global health burden, and sorafenib, a multi-kinase inhibitor, has shown effectiveness in the treatment of HCC and is considered as the first-line therapy for advanced HCC. However, the response to sorafenib varies among patients, and the development of drug resistance poses a prevalent obstacle. Ferroptosis, a newly characterized form of cell death featured by iron-dependent lipid peroxidation, has emerged as a critical player in the reaction to sorafenib therapy in HCC. The induction of ferroptosis has been shown to augment the anticancer benefits of sorafenib. However, it has also been observed to contribute to sorafenib resistance. This review presents a comprehensive and thorough analysis that elucidates the intricate relationship between ferroptosis and sorafenib over recent years, aiming to formulate effective therapeutic approaches for liver cancer. Based on this exploration, we propose innovative strategies intended to overcome sorafenib resistance via targeted modulation of ferroptosis.
Topics: Humans; Carcinoma, Hepatocellular; Sorafenib; Liver Neoplasms; Ferroptosis; Antineoplastic Agents; Cell Line, Tumor
PubMed: 38147732
DOI: 10.1016/j.biopha.2023.116074 -
Biomedicine & Pharmacotherapy =... Jul 2024Copper, an indispensable micronutrient, is implicated in numerous vital biological processes and is essential for all physiological activities. Recently, the discovery... (Review)
Review
Copper, an indispensable micronutrient, is implicated in numerous vital biological processes and is essential for all physiological activities. Recently, the discovery of a novel type of copper-dependent cell death, known as cuproptosis, has shed light on its role in cancer development. Extensive research is currently underway to unravel the mechanisms underlying cuproptosis and its correlation with various cancer types. In this review, we summarize the findings regarding the roles and mechanisms of cuproptosis in various cancer types, including colorectal cancer, lung cancer, gastric cancer, breast cancer, liver cancer and cutaneous melanoma. Furthermore, the effects of copper-related agents such as copper chelators and copper ionophores on cell proliferation, apoptosis, angiogenesis, tumor immunity, and chemotherapy resistance have been explored in cancer preclinical and clinical trials. These insights provide promising avenues for the development of prospective anticancer drugs aimed at inducing cuproptosis.
Topics: Humans; Neoplasms; Animals; Copper; Antineoplastic Agents; Apoptosis
PubMed: 38850661
DOI: 10.1016/j.biopha.2024.116874 -
European Journal of Medicinal Chemistry May 2024Cancer is a leading cause of death and a major health problem worldwide. While many effective anticancer agents are available, most drugs currently on the market are not... (Review)
Review
Cancer is a leading cause of death and a major health problem worldwide. While many effective anticancer agents are available, most drugs currently on the market are not specific, raising issues like the common side effects of chemotherapy. However, recent research hold promises for the development of more efficient and safer anticancer drugs. Quinoxaline and its derivatives are becoming recognized as a novel class of chemotherapeutic agents with activity against different tumors. The present review compiles and discusses studies concerning the therapeutic potential of the anticancer activity of quinoxaline derivatives, covering articles published between January 2018 and January 2023.
Topics: Quinoxalines; Humans; Antineoplastic Agents; Neoplasms; Animals; Molecular Structure; Drug Development; Cell Proliferation; Drug Discovery; Drug Screening Assays, Antitumor; Structure-Activity Relationship
PubMed: 38614060
DOI: 10.1016/j.ejmech.2024.116360 -
Molecules (Basel, Switzerland) Jul 2023This review uses the National Cancer Institute (NCI) COMPARE program to establish an extensive list of heterocyclic iminoquinones and quinones with similarities in... (Review)
Review
This review uses the National Cancer Institute (NCI) COMPARE program to establish an extensive list of heterocyclic iminoquinones and quinones with similarities in differential growth inhibition patterns across the 60-cell line panel of the NCI Developmental Therapeutics Program (DTP). Many natural products and synthetic analogues are revealed as potential NAD(P)H:quinone oxidoreductase 1 (NQO1) substrates, through correlations to dipyridoimidazo[5,4-]benzimidazoleiminoquinone (DPIQ), and as potential thioredoxin reductase (TrxR) inhibitors, through correlations to benzo[1,2,4]triazin-7-ones and pleurotin. The strong correlation to NQO1 infers the enzyme has a major influence on the amount of the active compound with benzo[]perimidines, phenoxazinones, benz[]pyrido[1,2-]indole-6,11-quinones, seriniquinones, kalasinamide, indolequinones, and furano[2,3-]naphthoquinones, hypothesised as prodrugs. Compounds with very strong correlations to known TrxR inhibitors had inverse correlations to the expression of both reductase enzymes, NQO1 and TrxR, including naphtho[2,3-][1,4]oxazepane-6,11-diones, benzo[]carbazole-1,4-diones, pyranonaphthoquinones (including kalafungin, nanaomycin A, and analogues of griseusin A), and discorhabdin C. Quinoline-5,8-dione scaffolds based on streptonigrin and lavendamycin can correlate to either reductase. Inhibitors of TrxR are not necessarily (imino)quinones, e.g., parthenolides, while oxidising moieties are essential for correlations to NQO1, as with the mitosenes. Herein, an overview of synthetic methods and biological activity of each family of heterocyclic imino(quinone) is provided.
Topics: United States; National Cancer Institute (U.S.); Quinones; Indolequinones; Oxidoreductases; NAD(P)H Dehydrogenase (Quinone); Antineoplastic Agents; Neoplasms
PubMed: 37446864
DOI: 10.3390/molecules28135202