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1.
Cancers (Basel) ; 15(10)2023 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-37345018

RESUMEN

Breast cancer continues to be the leading cause of cancer-related deaths among women worldwide. The most aggressive type of breast cancer is triple-negative breast cancer (TNBC). Indeed, not only does TNBC not respond well to several chemotherapeutic agents, but it also frequently develops resistance to various anti-cancer drugs, including taxane mitotic inhibitors. This necessitates the search for newer, more efficacious drugs. In this study, we synthesized two novel chromene derivatives (C1 and C2) and tested their efficacy against a battery of luminal type A and TNBC cell lines. Our results show that C1 and C2 significantly and specifically inhibited TNBC cell viability but had no effect on the luminal A cell type. In addition, these novel compounds induced mitotic arrest, cell multinucleation leading to senescence, and apoptotic cell death through the activation of the extrinsic pathway. We also showed that the underlying mechanisms for these actions of C1 and C2 involved inhibition of microtubule polymerization and disruption of the F-actin cytoskeleton. Furthermore, both compounds significantly attenuated migration of TNBC cells and inhibited angiogenesis in vitro. Finally, we performed an in silico analysis, which revealed that these novel variants bind to the colchicine binding site in ß-tubulin. Taken together, our data highlight the potential chemotherapeutic properties of two novel chromene compounds against TNBC.

2.
Antioxidants (Basel) ; 12(6)2023 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-37371889

RESUMEN

Reactive oxygen species (ROS) are metabolic byproducts that regulate various cellular processes. However, at high levels, ROS induce oxidative stress, which in turn can trigger cell death. Cancer cells alter the redox homeostasis to facilitate protumorigenic processes; however, this leaves them vulnerable to further increases in ROS levels. This paradox has been exploited as a cancer therapeutic strategy with the use of pro-oxidative drugs. Many chemotherapeutic drugs presently in clinical use, such as cisplatin and doxorubicin, induce ROS as one of their mechanisms of action. Further, various drugs, including phytochemicals and small molecules, that are presently being investigated in preclinical and clinical studies attribute their anticancer activity to ROS induction. Consistently, this review aims to highlight selected pro-oxidative drugs whose anticancer potential has been characterized with specific focus on phytochemicals, mechanisms of ROS induction, and anticancer effects downstream of ROS induction.

3.
Int J Mol Sci ; 23(12)2022 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-35743294

RESUMEN

The role of autophagy in lung cancer cells exposed to waterpipe smoke (WPS) is not known. Because of the important role of autophagy in tumor resistance and progression, we investigated its relationship with WP smoking. We first showed that WPS activated autophagy, as reflected by LC3 processing, in lung cancer cell lines. The autophagy response in smokers with lung adenocarcinoma, as compared to non-smokers with lung adenocarcinoma, was investigated further using the TCGA lung adenocarcinoma bulk RNA-seq dataset with the available patient metadata on smoking status. The results, based on a machine learning classification model using Random Forest, indicate that smokers have an increase in autophagy-activating genes. Comparative analysis of lung adenocarcinoma molecular signatures in affected patients with a long-term active exposure to smoke compared to non-smoker patients indicates a higher tumor mutational burden, a higher CD8+ T-cell level and a lower dysfunction level in smokers. While the expression of the checkpoint genes tested-PD-1, PD-L1, PD-L2 and CTLA-4-remains unchanged between smokers and non-smokers, B7-1, B7-2, IDO1 and CD200R1 were found to be higher in non-smokers than smokers. Because multiple factors in the tumor microenvironment dictate the success of immunotherapy, in addition to the expression of immune checkpoint genes, our analysis explains why patients who are smokers with lung adenocarcinoma respond better to immunotherapy, even though there are no relative differences in immune checkpoint genes in the two groups. Therefore, targeting autophagy in lung adenocarcinoma patients, in combination with checkpoint inhibitor-targeted therapies or chemotherapy, should be considered in smoker patients with lung adenocarcinoma.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Fumar en Pipa de Agua , Adenocarcinoma del Pulmón/genética , Autofagia/genética , Antígeno B7-H1/genética , Genómica , Humanos , Neoplasias Pulmonares/metabolismo , Microambiente Tumoral/genética
4.
Oncol Rep ; 47(4)2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35234267

RESUMEN

Pharmacological reactivation of tumor­suppressor protein p53 has acted as a promising strategy for more than 50% of human cancers that carry a non­functional mutant p53 (mutp53). p53 plays a critical role in preserving genomic integrity and DNA fidelity through numerous biological processes, including cell cycle arrest, DNA repair, senescence and apoptosis. By contrast, non­functional mutp53 compromises the aforementioned genome stabilizing mechanisms through gain of function, thereby increasing genomic instability in human cancers. Restoring the functional activity of p53 using both genetic and pharmacological approaches has gained prominence in targeting p53­mutated tumors. Thus, the present study aimed to investigate the reactivation of p53 in DNA repair mechanisms and the maintenance of genomic stability using PRIMA­1MET/APR­246 small molecules, in both MDA­MB­231 and MCF­7 breast cancer cell lines, which carry mutp53 and wild­type p53, respectively. Results of the present study revealed that reactivation of p53 through APR­246 led to an increase in the functional activity of DNA repair. Prolonged treatment of MDA­MB­231 cells with APR­246 in the presence of cisplatin led to a reduction in mutational accumulation, compared with cells treated with cisplatin alone. These findings demonstrated that APR­246 may act as a promising small molecule to control the genomic instability in p53­mutated tumors.


Asunto(s)
Neoplasias , Proteína p53 Supresora de Tumor , Inestabilidad Genómica , Humanos , Mutación , Neoplasias/patología , Quinuclidinas/farmacología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
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