Aldehyde dehydrogenase 1A1 confers erlotinib resistance via facilitating the reactive oxygen species-reactive carbonyl species metabolic pathway in lung adenocarcinomas

Lei, Hui‐Min; Zhang, Keren; Wang, Cong Hui; Wang, Yan; Zhuang, Guanglei; Lu, Liming; Zhang, Jian; Shen, Ying; Chen, Hongzhuan; Zhu, Liang

doi:10.7150/thno.35729

Cited by 51 publications

(39 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The aldehyde dehydrogenase 1A1 (ALDH1A1) enzyme, involved in alcohol metabolism, was recently shown to contribute to the development of erlotinib resistance with the acquisition of EMT/CSC features in lung cancer, and this was reverted on treatment with disulfiram, an ALDH1specific inhibitor [60]. In lung adenocarcinoma xenografts, continuous treatment with erlotinib showed erlotinib resistance in the tumors and combinatorial treatment with disulfiram increased the sensitivity of tumor growth inhibition.…”

Section: Disulfirammentioning

confidence: 99%

Targeting EMT in Cancer with Repurposed Metabolic Inhibitors

2020

View full text Add to dashboard Cite

Epithelial-to-mesenchymal transition (EMT) determines the most lethal features of cancer, metastasis formation and chemoresistance, and therefore represents an attractive target in oncology. However, direct targeting of EMT effector molecules is, in most cases, pharmacologically challenging. Since emerging research has highlighted the distinct metabolic circuits involved in EMT, we propose the use of metabolism-specific inhibitors, FDA approved or under clinical trials, as a drug repurposing approach to target EMT in cancer. Metabolism-inhibiting drugs could be coupled with standard chemo-or immunotherapy to combat EMT-driven resistant and aggressive cancers. Clinical Manifestations of EMTEMT, a classical developmental phenotypic plasticity program, is governed by the switching in the epithelial phenotype of a cell to mesenchymal form conferring various biological processes such as in gastrulation, neural crest migration, and wound healing [1]. Cancer being a highly heterogeneous disease known for its accumulations of various abnormalities in the cell, often recapitulates and manipulates the developmental EMT program in a partial and transient fashion to acquire advantageous features for its survival and propagation [2]. The EMT phenomenon is mediated through multiple transcription factors, aiding enhanced invasive ability, dissemination to distant sites, metastatic colonization, cancer stemness, and chemoresistance [3,4]. In some tissues, the EMT process has also been observed in the fundamental early steps of tumorigenesis [5,6]. Recent evidence highlighted that cancer cells that have undergone full EMT possess less metastatic potential, while cells in the partial or hybrid state inherently contain a high degree of plasticity and metastasis-initiating ability [7][8][9]. Dissemination of tumor cells as clusters by collective migration has also been proposed to be regulated through EMT-dependent mechanisms [10]. HighlightsEpithelial-to-mesenchymal transition (EMT), an embryonic phenotypic plasticity program, in cancer confers invasiveness, dissemination, and chemo/ immunotherapy resistance.

show abstract

Section: Disulfirammentioning

confidence: 99%

Targeting EMT in Cancer with Repurposed Metabolic Inhibitors

2020

View full text Add to dashboard Cite

show abstract

“…The Aldehyde dehydrogenase (ALDH) superfamily, consisting of 19 enzymes in humans, possess NAD(P)+-dependent enzymatic activity responsible for catalyzing the oxidation of aldehydes to carboxylic acids 8 , and thereby detoxify and protect cells from aldehydes and ROS accumulation 9 , 10 . These enzymes have diverse function in a wide range of biological processes, including vitamin-A metabolism into retinoic acid.…”

Section: Introductionmentioning

confidence: 99%

Aldehyde dehydrogenase inhibitors promote DNA damage in ovarian cancer and synergize with ATM/ATR inhibitors

Grimley¹,

Cole²,

Luong³

et al. 2021

Theranostics

View full text Add to dashboard Cite

Rationale : Aldehyde dehydrogenase (ALDH) enzymes are often upregulated in cancer cells and associated with therapeutic resistance. ALDH enzymes protect cells by metabolizing toxic aldehydes which can induce DNA double stand breaks (DSB). We recently identified a novel ALDH1A family inhibitor (ALDHi), 673A. We hypothesized that 673A, via inhibition of ALDH1A family members, could induce intracellular accumulation of genotoxic aldehydes to cause DSB and that ALDHi could synergize with inhibitors of the ATM and ATR, proteins which direct DSB repair. Methods : We used immunofluorescence to directly assess levels of the aldehyde 4-hydroxynonenal and comet assays to evaluate DSB. Western blot was used to evaluate activation of the DNA damage response pathways. Cell counts were performed in the presence of 673A and additional aldehydes or aldehyde scavengers. ALDH inhibition results were confirmed using ALDH1A3 CRISPR knockout. Synergy between 673A and ATM or ATR inhibitors was evaluated using the Chou-Talalay method and confirmed in vivo using cell line xenograft tumor studies. Results : The ALDHi 673A cellular accumulation of toxic aldehydes which induce DNA double strand breaks. This is exacerbated by addition of exogenous aldehydes such as vitamin-A (retinaldehyde) and ameliorated by aldehyde scavengers such as metformin and hydralazine. Importantly, ALDH1A3 knockout cells demonstrated increased sensitivity to ATM/ATR inhibitors. And, ALDHi synergized with inhibitors of ATM and ATR, master regulators of the DSB DNA damage response, both in vitro and in vivo. This synergy was evident in homologous recombination (HR) proficient cell lines. Conclusions : ALDHi can be used to induce DNA DSB in cancer cells and synergize with inhibitors the ATM/ATR pathway. Our data suggest a novel therapeutic approach to target HR proficient ovarian cancer cells.

show abstract

“…Further multicentric studies will need to be set to confirm our data. However, we believe that our report is important to amplify the knowledge regarding possible markers which have been already studied in non-small cell lung cancer showing a high impact of this marker on the prognosis, as well as also in responses to cancer treatments (9,10,13,33,34).…”

Section: Limitationsmentioning

confidence: 72%

“…In an interesting study published in 2014 by Nicholas Greco et al it has been demonstrated a significant correlation of aldehyde dehydrogenase (ALDH) activity and the presence/absence of distant metastases in ten consecutive cases of human bone sarcomas (34). Although angiosarcoma is more difficult to investigate for the rarity of this tumor into the population, it is important to understand the possible role that ALDH may have in this tumor for the possibility to set new target treatment against this aggressive malignant disease.…”

Section: Discussionmentioning

confidence: 99%