Aldehyde dehydrogenase inhibition combined with phenformin treatment reversed NSCLC through ATP depletion

Kang, Joo‐Hyon; Lee, Seon-Hyeong; Lee, Jae‐Seon; Nam, Boas; Seong, Tae Wha; Son, Jaekyoung; Jang, Hyonchol; Hong, Kyung Taek; Lee, Cheolju; Kim, Soo-Youl

doi:10.18632/oncotarget.10354

Cited by 52 publications

(79 citation statements)

References 27 publications

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“…Metformin is currently being tested in several clinical trials. A precursor molecule Phenformin, was taken off the market for diabetes due to its increased risk of lactic acidosis but has efficacy in against multiple cancer cell lines and preclinical models [40–44]. Phenformin is not reliant on transporters for cell entry and has increased potency for the mitochondrial membrane compared to metformin [45].…”

Section: Targeting the Electron Transport Chain (Etc)mentioning

confidence: 99%

Mitochondria in cancer metabolism, an organelle whose time has come?

Anderson

Ghiraldeli

Pardee

2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Mitochondria have long been controversial organelles in cancer. Early discoveries in cancer metabolism placed much emphasis on cytosolic contributions. Initial debate focused on if mitochondria had a role in cancer formation and progression at all. More recently the contributions of mitochondria to cancer development and progression have become firmly established. This has led to the identification of novel targets and inhibitors being studied as new therapeutic approaches. This review will summarize the role of mitochondria in cancer and highlight several agents under development.

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Section: Targeting the Electron Transport Chain (Etc)mentioning

confidence: 99%

Mitochondria in cancer metabolism, an organelle whose time has come?

Anderson

Ghiraldeli

Pardee

2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…Among different kinds of cancers, lung cancer remains the most common cancer throughout the world, regarding new cases and death for its high rates of morbidity and mortality [ 24 , 25 ]. Furthermore, non-small cell lung cancer (NSCLC) is the most common form of lung cancer [ 26 , 27 ]. Cancer chemotherapy offers effective treatment and developing novel anticancer drugs is a promising strategy to overcome cancer [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Structure Identification and In Vitro Anticancer Activity of Lathyrol-3-phenylacetate-5,15-diacetate

et al. 2017

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Natural products from the genus Euphorbia show attention-attracting activities, such as anticancer activity. In this article, classical isolation and structure identification were used in a study on Caper Euphorbia Seed. Subsequently, MTT and wound healing assays, flow cytometry, western blotting, Hoechst 33258 staining and fluorescence microscopy examination were applied to investigate the anticancer activity of the obtained compounds. In a result, lathyrol-3-phenyl- acetate-5,15-diacetate (deoxy Euphorbia factor L1, DEFL1) was isolated from Caper Euphorbia Seed. Moreover, the NMR signals were totally assigned. DEFL1 showed potent inhibition against lung cancer A549 cells, with an IC50 value of 17.51 ± 0.85 μM. Furthermore, DEFL1 suppressed wound healing of A549 cells in a concentration-dependent manner. Mechanically, DEFL1 induced apoptosis, with involvement of an increase of reactive oxygen species (ROS), decrease of mitochondrial membrane potential (ΔΨm), release of cytochrome c, activity raise of caspase-9 and 3. Characteristic features of apoptosis were observed by fluorescence microscopy. In summary, DEFL1 inhibited growth and induced apoptosis in lung cancer A549 cells via a mitochondrial pathway.

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“…Inhibition of ALDH cause ATP depletion that inhibits tumor growth in both in vitro and xenograft models [124,132]. Knockdown of ALDH significantly decreased NADH and ATP production in cancer [124,136]. Downregulation of ALDH1A3 sensitized cancer cells, prolonged G1 phase, shortened S phase and decreased cancer cell survival both in vitro and in vivo [135,137].…”

Section: Targeting Aldehyde Dehydrogenase (Aldh) Sensitizes Cancermentioning

confidence: 99%

NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

et al. 2020

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Actively proliferating cancer cells require sufficient amount of NADH and NADPH for biogenesis and to protect cells from the detrimental effect of reactive oxygen species. As both normal and cancer cells share the same NAD biosynthetic and metabolic pathways, selectively lowering levels of NAD(H) and NADPH would be a promising strategy for cancer treatment. Targeting nicotinamide phosphoribosyltransferase (NAMPT), a rate limiting enzyme of the NAD salvage pathway, affects the NAD and NADPH pool. Similarly, lowering NADPH by mutant isocitrate dehydrogenase 1/2 (IDH1/2) which produces D-2-hydroxyglutarate (D-2HG), an oncometabolite that downregulates nicotinate phosphoribosyltransferase (NAPRT) via hypermethylation on the promoter region, results in epigenetic regulation. NADPH is used to generate D-2HG, and is also needed to protect dihydrofolate reductase, the target for methotrexate, from degradation. NAD and NADPH pools in various cancer types are regulated by several metabolic enzymes, including methylenetetrahydrofolate dehydrogenase, serine hydroxymethyltransferase, and aldehyde dehydrogenase. Thus, targeting NAD and NADPH synthesis under special circumstances is a novel approach to treat some cancers. This article provides the rationale for targeting the key enzymes that maintain the NAD/NADPH pool, and reviews preclinical studies of targeting these enzymes in cancers.

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Aldehyde dehydrogenase inhibition combined with phenformin treatment reversed NSCLC through ATP depletion

Cited by 52 publications

References 27 publications

Mitochondria in cancer metabolism, an organelle whose time has come?

Mitochondria in cancer metabolism, an organelle whose time has come?

Structure Identification and In Vitro Anticancer Activity of Lathyrol-3-phenylacetate-5,15-diacetate

NAD- and NADPH-Contributing Enzymes as Therapeutic Targets in Cancer: An Overview

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