Design, synthesis characterization and biological evaluation of novel multi-isoform ALDH inhibitors as potential anticancer agents

Dinavahi, Saketh S.; Gowda, Raghavendra; Bazewicz, Christopher G.; Battu, Madhu Babu; Lin, Jingqiang; Chitren, Robert; Pandey, Manoj K.; Amin, Shantu; Robertson, Gavin P.; Gowda, Krishne

doi:10.1016/j.ejmech.2019.111962

Cited by 27 publications

(20 citation statements)

References 57 publications

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“…Aldi-6 is administered to the mice through osmotic mini pumps in order to improve bioavailability and reduce dose, resulting in no mortality, no systemic toxicity and no body weight loss reported during the study ( 90 ). Recently, a novel series of potent multi-ALDH inhibitors has been identified through ligand-based docking studies ( 91 ). Among the inhibitors tested, the KS100 compound showed to be the most potent against ALDH1A1, 2, and 3A1, displaying anti-proliferative activity and increasing ROS levels and lipid peroxidation in several in vitro cancer models.…”

Section: Targeting Aldehyde Dehydrogenases In Cancermentioning

confidence: 99%

“…Among the inhibitors tested, the KS100 compound showed to be the most potent against ALDH1A1, 2, and 3A1, displaying anti-proliferative activity and increasing ROS levels and lipid peroxidation in several in vitro cancer models. However, KS100 showed toxicity in vivo , leading to a significant weight loss after 14 days of treatment ( 91 ). In order to reduce/overcome toxicity, researchers have developed a nanoliposomal formulation of KS100, called NanoKS100 ( 92 ).…”

Section: Targeting Aldehyde Dehydrogenases In Cancermentioning

confidence: 99%

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Emerging Roles of Aldehyde Dehydrogenase Isoforms in Anti-cancer Therapy Resistance

et al. 2022

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Aldehyde dehydrogenases (ALDHs) are a family of detoxifying enzymes often upregulated in cancer cells and associated with therapeutic resistance. In humans, the ALDH family comprises 19 isoenzymes active in the majority of mammalian tissues. Each ALDH isoform has a specific differential expression pattern and most of them have individual functional roles in cancer. ALDHs are overexpressed in subpopulations of cancer cells with stem-like features, where they are involved in several processes including cellular proliferation, differentiation, detoxification and survival, participating in lipids and amino acid metabolism and retinoic acid synthesis. In particular, ALDH enzymes protect cancer cells by metabolizing toxic aldehydes in less reactive and more soluble carboxylic acids. High metabolic activity as well as conventional anticancer therapies contribute to aldehyde accumulation, leading to DNA double strand breaks (DSB) through the generation of reactive oxygen species (ROS) and lipid peroxidation. ALDH overexpression is crucial not only for the survival of cancer stem cells but can also affect immune cells of the tumour microenvironment (TME). The reduction of ROS amount and the increase in retinoic acid signaling impairs immunogenic cell death (ICD) inducing the activation and stability of immunosuppressive regulatory T cells (Tregs). Dissecting the role of ALDH specific isoforms in the TME can open new scenarios in the cancer treatment. In this review, we summarize the current knowledge about the role of ALDH isoforms in solid tumors, in particular in association with therapy-resistance.

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Section: Targeting Aldehyde Dehydrogenases In Cancermentioning

confidence: 99%

Section: Targeting Aldehyde Dehydrogenases In Cancermentioning

confidence: 99%

Emerging Roles of Aldehyde Dehydrogenase Isoforms in Anti-cancer Therapy Resistance

et al. 2022

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“…Several studies have targeted multi-isoform ALDH, including ALDH3A1. (Dinavahi et al, 2020). This cytotoxic effect caused by ALDH loss was accompanied by increased reactive oxygen species and lipid peroxidation, indicating greater oxidative stress.…”

Section: Discussionmentioning

confidence: 97%

Nuclear Factor Erythroid 2–Related Factor 2 Depletion Sensitizes Pancreatic Cancer Cells to Gemcitabine via Aldehyde Dehydrogenase 3a1 Repression

Matsumoto

Hamada

Tanaka

et al. 2021

J Pharmacol Exp Ther

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As the central regulator of the oxidative stress response, nuclear factor erythroid 2-related factor 2 (Nrf2) is attracting great interest as a therapeutic target for various cancers, and the possible clinical applications of novel Nrf2 inhibitors have been explored in Nrf2-activated cancers. In the present study, we specifically investigated halofuginone, which is derived from a natural plant alkaloid. We found that halofuginone administration decreased the number of pancreatic intraepithelial neoplasias in pancreas-specific Kras and p53 mutant (KPC) mice. In Nrf2-activated pancreatic cancer cell lines established from KPC mice, halofuginone rapidly depleted Nrf2 in Nrf2-activated cancer cells. Both in vitro and in vivo, it sensitized Nrf2-activated pancreatic cancer cells to gemcitabine, which is the first-line chemotherapy in clinical practice. In our mechanistic study, we found that halofuginone downregulated ALDH3A1 in mouse pancreatic cancer cells. The Nrf2 inducer diethyl maleate upregulated ALDH3A1, and knockdown of Aldh3a1 sensitized Nrf2-activated cancer cells to gemcitabine, strongly suggesting that ALDH3A1 is regulated by Nrf2 and that it contributes to gemcitabine resistance. The current study demonstrated the therapeutic benefits of halofuginone in Nrf2-activated pancreatic cancers.

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“…In BTZ-resistant (ANBL6-BR) cells, ALDH1 + cells constitute a larger proportion of the population than in wild-type (ANBL6) cells, and ALDH1A1 is highly expressed in BTZ-resistant cells [ 42 ]. ALDH-activity detection has been used to reflect the stemness of MM cells in the study of drug killing-effect detection, surface markers, and characteristic proteins identification in the MM stem cell-like population [ 18 , 43 , 44 , 45 ]…”

Section: Markers Of Mmscs and Drugs Targeting Themmentioning

confidence: 99%

Identification and Characterization of Multiple Myeloma Stem Cell-Like Cells

Guo

Wang

Chen

et al. 2021

Cancers

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Multiple myeloma (MM) is a B-cell tumor of the blood system with high incidence and poor prognosis. With a further understanding of the pathogenesis of MM and the bone marrow microenvironment, a variety of adjuvant cell therapies and new drugs have been developed. However, the drug resistance and high relapse rate of MM have not been fundamentally resolved. Studies have shown that, in patients with MM, there is a type of poorly differentiated progenitor cell (MM stem cell-like cells, MMSCs). Although there is no recognized standard for identification and classification, it is confirmed that they are closely related to the drug resistance and relapse of MM. This article therefore systematically summarizes the latest developments in MMSCs with possible markers of MMSCs, introduces the mechanism of how MMSCs work in MM resistance and recurrence, and discusses the active pathways that related to stemness of MM.

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Design, synthesis characterization and biological evaluation of novel multi-isoform ALDH inhibitors as potential anticancer agents

Cited by 27 publications

References 57 publications

Emerging Roles of Aldehyde Dehydrogenase Isoforms in Anti-cancer Therapy Resistance

Emerging Roles of Aldehyde Dehydrogenase Isoforms in Anti-cancer Therapy Resistance

Nuclear Factor Erythroid 2–Related Factor 2 Depletion Sensitizes Pancreatic Cancer Cells to Gemcitabine via Aldehyde Dehydrogenase 3a1 Repression

Identification and Characterization of Multiple Myeloma Stem Cell-Like Cells

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