Effects of chloroquine and hydroxychloroquine on the sensitivity of pancreatic cancer cells to targeted therapies.

Autor: McCubrey JA; Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27858, USA. Electronic address: mccubreyj@ecu.edu., Abrams SL; Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, 27858, USA., Follo MY; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy., Manzoli L; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy., Ratti S; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy., Martelli AM; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy., Cervello M; Institute for Biomedical Research and Innovation, National Research Council (CNR), Palermo, Italy.
Jazyk: angličtina
Zdroj: Advances in biological regulation [Adv Biol Regul] 2023 Jan; Vol. 87, pp. 100917. Date of Electronic Publication: 2022 Sep 29.
DOI: 10.1016/j.jbior.2022.100917
Abstrakt: Approaches to improve pancreatic cancer therapy are essential as this disease has a very bleak outcome. Approximately 80% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is a cancer which is difficult to effectively treat as it is often detected late in the disease process. Almost all PDACs (over 90%) have activating mutations in the GTPase gene KRAS. These mutations result in constitutive KRas activation and the mobilization of downstream pathways such as the Raf/MEK/ERK pathway. Small molecule inhibitors of key components of the KRas/Raf/MEK/ERK pathways as well as monoclonal antibodies (MoAbs) specific for upstream growth factor receptors such insulin like growth factor-1 receptor (IGF1-R) and epidermal growth factor receptors (EGFRs) have been developed and have been evaluated in clinical trials. An additional key regulatory gene frequently mutated (∼75%) in PDAC is the TP53 tumor suppressor gene which controls the transcription of multiple genes involved in cell cycle progression, apoptosis, metabolism, cancer progression and other growth regulatory processes. Small molecule mutant TP53 reactivators have been developed which alter the structure of mutant TP53 protein and restore some of its antiproliferative activities. Some mutant TP53 reactivators have been examined in clinical trials with patients with mutant TP53 genes. Inhibitors to the TP53 negative regulator Mouse Double Minute 2 (MDM2) have been developed and analyzed in clinical trials. Chloroquine and hydroxychloroquine are established anti-malarial and anti-inflammatory drugs that also prevent the induction of autophagy which can have effects on cancer survival. Chloroquine and hydroxychloroquine have also been examined in various clinical trials. Recent studies are suggesting effective treatment of PDAC patients may require chemotherapy as well as targeting multiple pathways and biochemical processes.
Competing Interests: Declaration of competing interest We hereby declare that no authors have any conflicts of interest with publication of this manuscript.
(Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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