α,β-Acetylenic Amino Thiolester Inhibitors of Aldehyde Dehydrogenases 1&amp;3: Suppressors of Apoptogenic Aldehyde Oxidation and Activators of Apoptosis

Fournet, G.; Martin, G.; Quash, G.

doi:10.2174/092986713804910148

Cited by 4 publications

(9 citation statements)

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“…Numerous ALDH inhibitors have been developed in the fight against cancer. These include DEAB, DIMATE, disulfiram, CM026, CM037, NCT‐501, CVT‐10216, ALDH423 and CB29 . Among these, the broad‐spectrum ALDH inhibitors DEAB, DIMATE and disulfiram either remain in the early stages of development or are limited by their toxicity, while the isoform‐specific ALDH inhibitors CM026, CM037, NCT‐501, CVT‐10216, ALDH423 and CB29 have limited efficacy .…”

Section: Introductionmentioning

confidence: 99%

Aldehyde dehydrogenase in regulatory T‐cell development, immunity and cancer

et al. 2018

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The role of aldehyde dehydrogenase (ALDH) in carcinogenesis and resistance to cancer therapies is well known. Mounting evidence also suggests a potentially important role for ALDH in the induction and function of regulatory T (Treg) cells. Treg cells are important cells of the immune system involved in promoting immune tolerance and preventing aberrant immune responses to beneficial or non-harmful antigens. However, Treg cells also impair tumor immunity, leading to the progression of various carcinomas. ALDH expression and the subsequent production of retinoic acid by numerous cells, including dendritic cells, macrophages, eosinophils and epithelial cells, seems important in Treg induction and function in multiple organ systems. This is particularly evident in the gastrointestinal tract, pulmonary tract and skin, which are exposed to a myriad of environmental antigens and represent interfaces between the human body and the outside world. Expression of ALDH in Treg cells themselves may also be involved in the proliferation of these cells and resistance to certain cytotoxic therapies. Hence, inhibition of ALDH expression may be useful to treat cancer. Besides the direct effect of ALDH inhibition on carcinogenesis and resistance to cancer therapies, inhibition of ALDH could potentially augment the immune response to tumor antigens by inhibiting Treg induction, function and ability to promote immune tolerance to tumor cells in multiple cancer types.

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Section: Introductionmentioning

confidence: 99%

Aldehyde dehydrogenase in regulatory T‐cell development, immunity and cancer

et al. 2018

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“…Importantly, KS100 exhibited a >60-fold increased potency toward ALDH3A1 compared with DEAB. Further, KS100 has an approximately 24-fold and approximately 21-fold increased potency toward ALDH1A1 and 3A1, respectively, compared with DIMATE (22,60,62). Finally, KS100 has an approximately 3-fold and 5-fold increased potency toward ALDH1A1 and 3A1, respectively, compared with aldi-6, while having slightly less potency toward ALDH2 (24).…”

Section: Discussionmentioning

confidence: 94%

“…Increased metabolism of toxic aldehydes through ALDH upregulation can facilitate cancer progression and therapy resistance (9,17,53). Thus, numerous ALDH inhibitors have been developed as anticancer agents and show variable efficacy in the treatment of breast (54)(55)(56), lung (18,23,25,33), hepatocellular (57), ovarian (26,29,30,58,59), gastric (25), colon (25), prostate (60), and HNSCC (24,25,28,61) as well as glioblastoma (18,33), leukemia (22), and melanoma (62). Elevated ALDH activity is typically a composite of multiple ALDH isoforms (14,15).…”

Section: Discussionmentioning

confidence: 99%

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Development of a Novel Multi-Isoform ALDH Inhibitor Effective as an Antimelanoma Agent

Dinavahi

Gowda

Bazewicz

et al. 2020

Molecular Cancer Therapeutics

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The aldehyde dehydrogenases (ALDH) are a major family of detoxifying enzymes that contribute to cancer progression and therapy resistance. ALDH overexpression is associated with a poor prognosis in many cancer types. The use of multi-ALDH isoform or isoform-specific ALDH inhibitors as anticancer agents is currently hindered by the lack of viable candidates. Most multi-ALDH isoform inhibitors lack bioavailability and are nonspecific or toxic, whereas most isoform-specific inhibitors are not effective as monotherapy due to the overlapping functions of ALDH family members. The present study details the development of a novel, potent, multiisoform ALDH inhibitor, called KS100. The rationale for drug development was that inhibition of multiple ALDH isoforms might be more efficacious for cancer compared with isoform-specific inhibition. Enzymatic IC 50 s of KS100 were 207, 1,410, and 240 nmol/L toward ALDH1A1, 2, and 3A1, respectively. Toxicity of KS100 was mitigated by development of a nanoliposomal formulation, called NanoKS100. NanoKS100 had a loading efficiency of approximately 69% and was stable long-term. NanoKS100 was 5-fold more selective for killing melanoma cells compared with normal human fibroblasts. NanoKS100 administered intravenously at a submaximal dose (3-fold lower) was effective at inhibiting xenografted melanoma tumor growth by approximately 65% without organ-related toxicity. Mechanistically, inhibition by KS100 significantly reduced total cellular ALDH activity to increase reactive oxygen species generation, lipid peroxidation, and accumulation of toxic aldehydes leading to apoptosis and autophagy. Collectively, these data suggest the successful preclinical development of a nontoxic, bioavailable, nanoliposomal formulation containing a novel multi-ALDH isoform inhibitor effective in the treatment of cancer.

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“…The evidence that HPA is really an apoptogenic aldehyde like malondialdehyde or 4-hydroxynonenal [17] is still pending but the experiments of Iyer [14] are suggestive for this function.…”

Section: Discussionmentioning

confidence: 99%

Enzyme Catalyzed Decomposition of 4-Hydroxycyclophosphamide

Voelcker¹

2017

TOPROCJ

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According to general doctrine [1] canceroselectivity of Cyclophosphamide is based on different activities of the 4-hydroxycyclophosphamide (OHCP) detoxifying cellular enzyme aldehyde dehydrogenase in tumor and normal cells. Aldehyde dehydrogenase converts the OHCP tautomere aldophosphamide (ALDO) to the non-cytotoxic carboxyphosphamide. Due to different activities of the detoxifying enzyme more cytotoxic phosporamide mustard (PAM) is spontaneously released from OHCP/ALDO in tumor cells. PAM unfolds its cytotoxic activity by forming intrastrand and interstrand DNA crosslinks. This hypothesis is supported by in vitro experiments which show inverse correlations of aldehyde dehydrogenase activity and sensitivity of tumor cells against activated congeners of cyclophosphamide like mafosfamide which hydrolyses within a few minutes to OHCP. In protein free rat serum ultrafiltrate however free OHCP and its coexisting tautomer ALDO are stable compounds. Its half-life in protein free rat serum ultrafiltrate (pH7, 37 o C) is more than 20 h. Contrary to protein free ultrafiltrate in whole serum ALDO is enzymatically decomposed to PAM and 3-hydroxypropionaldehyde (HPA) within minutes. The decomposing enzyme was identified as 3´-5´ phosphodiesterase, the Michaelis constant was determined to be 10 -3 M in human serum.The experiments presented clearly demonstrate that ALDO is not only cleaved base catalyzed yielding acrolein and PAM [2, 3] but also cleaved enzymatically by serum phosphodiesterases yielding HPA and PAM. It is discussed that the reason of the high canceroselectivity of cyclophosphamide is not only due to enrichment of OHCP/ALDO in tumor cells due to less detoxification of ALDO in tumor cells than in normal cells. It is discussed that there is a good reason for an additional mechanism namely the amplification of apoptosis of PAM damaged cells by HPA.A two step mechanism for the mechanism of action of OHCP/ALDO is discussed. During the first step, the DNA is damaged by alkylation by PAM. During the second step the cell containing damaged DNA is eliminated by apoptosis, supported by HPA.

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α,β-Acetylenic Amino Thiolester Inhibitors of Aldehyde Dehydrogenases 1&3: Suppressors of Apoptogenic Aldehyde Oxidation and Activators of Apoptosis

Cited by 4 publications

References 68 publications

Aldehyde dehydrogenase in regulatory T‐cell development, immunity and cancer

Aldehyde dehydrogenase in regulatory T‐cell development, immunity and cancer

Development of a Novel Multi-Isoform ALDH Inhibitor Effective as an Antimelanoma Agent

Enzyme Catalyzed Decomposition of 4-Hydroxycyclophosphamide

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