Lima Keli, de Miranda Lívia Bassani Lins, Del Milagro Bernabe Garnique Anali, de Almeida Bruna Oliveira, do Nascimento Mariane Cristina, Alcântara Guilherme Augusto Sousa, Machado-Santelli Glaucia Maria, Rego Eduardo Magalhães, Machado-Neto João Agostinho
Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology Division, Faculdade de Medicina, University of São Paulo, São Paulo 01246-903, Brazil.
Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo 05508-000, Brazil.
Cancers (Basel). 2023 Jul 29;15(15):3866. doi: 10.3390/cancers15153866.
Significant advances in understanding the molecular complexity of the development and progression of pancreatic cancer have been made, but this disease is still considered one of the most lethal human cancers and needs new therapeutic options. In the present study, the antineoplastic effects of AD80, a multikinase inhibitor, were investigated in models of pancreatic cancer. AD80 reduced cell viability and clonogenicity and induced polyploidy in pancreatic cancer cells. At the molecular level, AD80 reduced RPS6 and histone H3 phosphorylation and induced γH2AX and PARP1 cleavage. Additionally, the drug markedly decreased AURKA phosphorylation and expression. In PANC-1 cells, AD80 strongly induced autophagic flux (consumption of LC3B and SQSTM1/p62). AD80 modulated 32 out of 84 autophagy-related genes and was associated with vacuole organization, macroautophagy, response to starvation, cellular response to nitrogen levels, and cellular response to extracellular stimulus. In 3D pancreatic cancer models, AD80 also effectively reduced growth independent of anchorage and cell viability. In summary, AD80 induces mitotic aberrations, DNA damage, autophagy, and apoptosis in pancreatic cancer cells. Our exploratory study establishes novel targets underlying the antineoplastic activity of the drug and provides insights into the development of therapeutic strategies for this disease.
在理解胰腺癌发生和发展的分子复杂性方面已取得重大进展，但这种疾病仍被认为是最致命的人类癌症之一，需要新的治疗选择。在本研究中，研究了多激酶抑制剂AD80在胰腺癌模型中的抗肿瘤作用。AD80降低了胰腺癌细胞的活力和克隆形成能力，并诱导了多倍体形成。在分子水平上，AD80降低了RPS6和组蛋白H3的磷酸化，并诱导了γH2AX和PARP1的裂解。此外，该药物显著降低了AURKA的磷酸化和表达。在PANC-1细胞中，AD80强烈诱导自噬流（LC3B和SQSTM1/p62的消耗）。AD80调节了84个自噬相关基因中的32个，与液泡组织、巨自噬、对饥饿的反应、细胞对氮水平的反应以及细胞对细胞外刺激的反应有关。在三维胰腺癌模型中，AD80也有效地降低了不依赖锚定的生长和细胞活力。总之，AD80在胰腺癌细胞中诱导有丝分裂异常、DNA损伤、自噬和凋亡。我们的探索性研究确定了该药物抗肿瘤活性的新靶点，并为这种疾病的治疗策略开发提供了见解。
