Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer

Abstract

Apurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites). In non-small cell lung cancer (NSCLC), APE1 is highly expressed and associated with poor patient prognosis. The suppression of APE1 could lead to the accumulation of unrepaired DNA damage in cells. Therefore, APE1 is viewed as an important marker of malignant tumors and could serve as a potent target for the development of antitumor drugs. In this study, we performed a high-throughput virtual screening of a small-molecule library using the three-dimensional structure of APE1 protein. Using the AP site cleavage assay and a cell survival assay, we identified a small molecular compound, NO.0449-0145, to act as an APE1 inhibitor. Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460. This inhibitor was also able to impede cancer progression in an NCI-H460 mouse model. Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines. These findings underscore the importance of APE1 as a therapeutic target in NSCLC and offer a paradigm for the development of small-molecule drugs that target key DNA repair proteins for the treatment of NSCLC and other cancers.

METTL3 promotes homologous recombination repair and modulates chemotherapeutic response in breast cancer by regulating the EGF/RAD51 axis

“…A large number of studies have implicated dysfunctional DNA repair proteins, such as BRCA1, RAD51, FEN1, and Polβ, in BC initiation and progression ( Li et al, 2021 ; Lu et al, 2020 ; Martin et al, 2007 ; Thacker, 2005 ; Wang et al, 2019 ; Wang et al, 2020b ; Xia et al, 2021 ). Elevated DNA repair activity contributes to drug resistance and limits the efficacy of chemotherapeutic agents ( Long et al, 2021 ; Lu et al, 2020 ). Thus, targeting the DDR key proteins such as BRCA1 and BRCA2 is a potential effective therapeutic strategy for mono- or combination therapy.…”

Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment

“…In vivo studies demonstrated inhibition of NSCLC progression in mice. These promising results following APE1 inhibition prompted further investigations into various small molecule inhibitors of the protein [131]. Gossypol is an inhibitor of APE1 involved in a phase III trial (ClinicalTrials.gov Identifier: NCT01977209) to assess its ability to improve the sensitivity of cisplatin-based chemotherapy in NSCLC patients with high APE1 expression (Table 1).…”

Identification of an Aging-Related Gene Signature in Predicting Prognosis and Indicating Tumor Immune Microenvironment in Breast Cancer

“…The different expressions of immune checkpoints between high- and low-risk groups could be used to predict the clinical response of corresponding inhibitors and provide new insights into clinical treatment. The NCI-60 database, consisting of 60 different cancer cell lines from nine different types of tumors, was performed to investigate drug sensitivity through the CallMiner software ( ) ( 27 ). Finally, the Pearson correlation analysis was utilized to detect the association between the prognostic AG expression and 263 drugs approved by the Food and Drug Administration (FDA).…”