| Full text | |
| Author(s): |
Lins de Miranda, Livia Bassani
;
Lima, Keli
;
Coelho-Silva, Juan Luiz
;
Traina, Fabiola
;
Kobayashi, Susumu S.
;
Machado-Neto, Joao Agostinho
Total Authors: 6
|
| Document type: | Journal article |
| Source: | SCIENTIFIC REPORTS; v. 12, n. 1, p. 11-pg., 2022-10-12. |
| Abstract | |
Combination therapies or multi-targeted drugs have been pointed out as an option to prevent the emergence of resistant clones, which could make long-term treatment more effective and translate into better clinical outcomes for cancer patients. The NT157 compound is a synthetic tyrphostin that leads to long-term inhibition of IGF1R/IRS1-2-, STAT3- and AXL-mediated signaling pathways. Given the importance of these signaling pathways for the development and progression of lung cancer, this disease becomes an interesting model for generating preclinical evidence on the cellular and molecular mechanisms underlying the antineoplastic activity of NT157. In lung cancer cells, exposure to NT157 decreased, in a dose-dependent manner, cell viability, clonogenicity, cell cycle progression and migration, and induced apoptosis (p < 0.05). In the molecular scenario, NT157 reduced expression of IRS1 and AXL and phosphorylation of p38 MAPK, AKT, and 4EBP1. Besides, NT157 decreased expression of oncogenes BCL2, CCND1, MYB, and MYC and increased genes related to cellular stress and apoptosis, JUN, BBC3, CDKN1A, CDKN1B, FOS, and EGR1 (p < 0.05), favoring a tumor-suppressive cell signaling network in the context of lung cancer. Of note, JNK was identified as a key kinase for NT157-induced IRS1 and IRS2 phosphorylation, revealing a novel axis involved in the mechanism of action of the drug. NT157 also presented potentiating effects on EGFR inhibitors in lung cancer cells. In conclusion, our preclinical findings highlight NT157 as a putative prototype of a multitarget drug that may contribute to the antineoplastic arsenal against lung cancer. (AU) | |
| FAPESP's process: | 19/23864-7 - Comprehensive analysis of genomic data for identification and validation of novel therapeutic targets involved in cellular cytoskeleton regulation in acute Leukemia |
| Grantee: | João Agostinho Machado Neto |
| Support Opportunities: | Regular Research Grants |
| FAPESP's process: | 20/12748-3 - Study regarding NT157 effects, a multitarget antineoplastic, in lung cancer cell models |
| Grantee: | Lívia Bassani Lins de Miranda |
| Support Opportunities: | Scholarships in Brazil - Scientific Initiation |
| FAPESP's process: | 21/11606-3 - Investigation of the antineoplastic effects of novel PIP4K2 and HDAC inhibitors in hematologic malignancies |
| Grantee: | João Agostinho Machado Neto |
| Support Opportunities: | Regular Research Grants |