Design, Synthesis and Biological Evaluation of Novel MDH Inhibitors Targeting Tumor Microenvironment

Godesi, Sreenivasulu; Han, Jeong-Ran; Kim, Jang Keun; Kwak, Dong-Ik; Lee, Joohan; Nada, Hossam; Kim, Minkyoung; Yang, Hyun-A; Im, Joo-Young; Ban, Hyun Seung; Lee, Chang Hoon; Choi, Yong Seok; Won, Misun; Lee, Kyeong

doi:10.3390/ph16050683

Cited by 7 publications

(1 citation statement)

References 34 publications

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“…Other cytosolic enzymes, including Malate dehydrogenase 1 (MDH1) and Isocitrate Dehydrogenase 1 (IDH1), are also involved in the production of NADPH. The inhibition of MDH1, a key enzyme in the glutamine catabolic pathway, has been recently reported to sensitize cancer cells to oxidative stress, decreasing cell proliferation and inhibiting tumor growth in vivo [31], and its targeting is being suggested as a therapeutic approach [32]. Similarly, IDH1 has been related to tumor development, and changes in IDH1 expression levels or gene mutations have been reported in several tumors [33,34].…”

Section: Foxo3a Impairs Nadph Production Through the Pentose Phosphat...mentioning

confidence: 99%

FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity

Fiorillo,

Ricci,

Fava

et al. 2023

Cells

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Tamoxifen-resistant breast cancer cells (TamR-BCCs) are characterized by an enhanced metabolic phenotype compared to tamoxifen-sensitive cells. FoxO3a is an important modulator of cell metabolism, and its deregulation has been involved in the acquisition of tamoxifen resistance. Therefore, tetracycline-inducible FoxO3a was overexpressed in TamR-BCCs (TamR/TetOn-AAA), which, together with their control cell line (TamR/TetOn-V), were subjected to seahorse metabolic assays and proteomic analysis. FoxO3a was able to counteract the increased oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) observed in TamR by reducing their energetic activity and glycolytic rate. FoxO3a caused glucose accumulation, very likely by reducing LDH activity and mitigated TamR biosynthetic needs by reducing G6PDH activity and hindering NADPH production via the pentose phosphate pathway (PPP). Proteomic analysis revealed a FoxO3a-dependent marked decrease in the expression of LDH as well as of several enzymes involved in carbohydrate metabolism (e.g., Aldolase A, LDHA and phosphofructokinase) and the analysis of cBioPortal datasets of BC patients evidenced a significant inverse correlation of these proteins and FoxO3a. Interestingly, FoxO3a also increased mitochondrial biogenesis despite reducing mitochondrial functionality by triggering ROS production. Based on these findings, FoxO3a inducing/activating drugs could represent promising tools to be exploited in the management of patients who are refractory to antiestrogen therapy.

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Section: Foxo3a Impairs Nadph Production Through the Pentose Phosphat...mentioning

confidence: 99%

FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity

Fiorillo,

Ricci,

Fava

et al. 2023

Cells

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Inducing disulfidptosis in tumors:potential pathways and significance

Mi,

Kong,

Chen

et al. 2024

MedComm

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Regulated cell death (RCD) is crucial for the elimination of abnormal cells. In recent years, strategies aimed at inducing RCD, particularly apoptosis, have become increasingly important in cancer therapy. However, the ability of tumor cells to evade apoptosis has led to treatment resistance and relapse, prompting extensive research into alternative death processes in cancer cells. A recent study identified a novel form of RCD known as disulfidptosis, which is linked to disulfide stress. Cancer cells import cystine from the extracellular environment via solute carrier family 7 member 11 (SLC7A11) and convert it to cysteine using nicotinamide adenine dinucleotide phosphate (NADPH). When NADPH is deficient or its utilization is impaired, cystine accumulates, leading to the formation of disulfide bonds in the actin cytoskeleton, triggering disulfidptosis. Disulfidptosis reveals a metabolic vulnerability in tumors, offering new insights into cancer therapy strategies. This review provides a detailed overview of the mechanisms underlying disulfidptosis, the current research progress, and limitations. It also highlights innovative strategies for inducing disulfidptosis and explores the potential of combining these approaches with traditional cancer therapies, particularly immunotherapy, to expedite clinical translation.

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