9-ING-41, a small molecule inhibitor of GSK-3beta, potentiates the effects of anticancer therapeutics in bladder cancer

Kuroki, Hiroo; Anraku, Tsutomu; Kazama, Akira; Bilim, Vladimir; Tasaki, Masayuki; Schmitt, Daniel; Mazar, Andrew P.; Giles, Francis J.; Ugolkov, Andrey; Tomita, Yoshihiko

doi:10.1038/s41598-019-56461-4

Cited by 37 publications

(38 citation statements)

References 34 publications

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“…Our results point to the effects that both WT-GSK-3β and KD-GSK-3β can have on sensitivity of certain pancreatic and breast cancer cells to chemotherapy and targeted therapy. These results are important as chemotherapeutic drugs can alter the activity of GSK-3β [3,86]. Therefore, without knowing the downstream consequences, suppression or activation of GSK-3β may change the sensitivity to targeted therapeutics.…”

Section: Discussionmentioning

confidence: 99%

GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals

Abrams

Akula

Meher

et al. 2021

Cells

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Glycogen synthase kinase-3 (GSK-3) is a regulator of signaling pathways. KRas is frequently mutated in pancreatic cancers. The growth of certain pancreatic cancers is KRas-dependent and can be suppressed by GSK-3 inhibitors, documenting a link between KRas and GSK-3. To further elucidate the roles of GSK-3β in drug-resistance, we transfected KRas-dependent MIA-PaCa-2 pancreatic cells with wild-type (WT) and kinase-dead (KD) forms of GSK-3β. Transfection of MIA-PaCa-2 cells with WT-GSK-3β increased their resistance to various chemotherapeutic drugs and certain small molecule inhibitors. Transfection of cells with KD-GSK-3β often increased therapeutic sensitivity. An exception was observed with cells transfected with WT-GSK-3β and sensitivity to the BCL2/BCLXL ABT737 inhibitor. WT-GSK-3β reduced glycolytic capacity of the cells but did not affect the basal glycolysis and mitochondrial respiration. KD-GSK-3β decreased both basal glycolysis and glycolytic capacity and reduced mitochondrial respiration in MIA-PaCa-2 cells. As a comparison, the effects of GSK-3 on MCF-7 breast cancer cells, which have mutant PIK3CA, were examined. KD-GSK-3β increased the resistance of MCF-7 cells to chemotherapeutic drugs and certain signal transduction inhibitors. Thus, altering the levels of GSK-3β can have dramatic effects on sensitivity to drugs and signal transduction inhibitors which may be influenced by the background of the tumor.

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Section: Discussionmentioning

confidence: 99%

GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals

Abrams

Akula

Meher

et al. 2021

Cells

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“…The protective autophagy-inducing properties of 9-ING-41 were demonstrated in bladder cancer cells by Kuroki et al. 55 They pointed out that combined treatments with 9-ING-41 and CQ enhanced the toxic effect of 9-ING-41 on bladder cancer cells. They further reported that in chemo-resistant T24 and HT1376 bladder cancer cell lines, 9-ING-41 increased the anti-tumor effect of cisplatin and GC.…”

Section: Survival Effects Of Autophagy On Bladder Cancer Cellsmentioning

confidence: 98%

Contrast effects of autophagy in the treatment of bladder cancer

Konac

Kurman

Baltacı

2020

Exp Biol Med (Maywood)

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Bladder cancer is a disease that negatively affects patients’ quality of life, but treatment options have remained unchanged for a long time. Although promising results have been achieved with current bladder cancer treatments, cancer recurrence, progression, and therapy resistance are the most severe problems preventing the efficiency of bladder cancer treatments. Autophagy refers to an evolutionarily conserved catabolic process in which proteins, damaged organelles, and cytoplasmic components are degraded by lysosomal enzymes. Autophagy regulates the therapeutic response to the chemotherapy drugs, thus determining the effect of therapy on cancer cells. Autophagy is a stress-induced cell survival mechanism and its excessive stimulation can cause resistance of tumor cells to therapeutic agents. Depending on the conditions, an increase in autophagy may cause treatment resistance or autophagic cell death, and it is related to important anti-cancer mechanisms, such as apoptosis. Therefore, understanding the roles of autophagy under different conditions is important for designing effective anti-cancer agents. The dual role of autophagy in cancer has attracted considerable attention in respect of bladder cancer treatment. In this review, we summarize the basic characteristics of autophagy, including its mechanisms, regulation, and functions, and we present examples from current studies concerning the dual role of autophagy in bladder cancer progression and therapy. Impact statement Autophagy acts as an intracellular recycling system. Infection and mitochondrial damage, maintaining cellular homeostasis, orchestrating nutrient stress, hypoxia, and oxidative stress are some of the physiological roles associated with autophagy. Autophagy has also context-dependent roles in cancer. Autophagy has a significant impact on tumor initiation and promotion, with both tumor-suppressive and tumor-promoting roles. Unfortunately, conventional systemic chemotherapy for cancer therapy has been reported to have primary limitations such as chemo-resistance of targeted cells. The cytoprotective role of autophagy has been postulated as one of the causes of this resistance. Hence, combination therapy using autophagy inhibitors has recently started to emerge as a noteworthy strategy in the treatment of cancer. Therefore, targeting the autophagy pathways may be a potential therapeutic strategy for addressing cancer progression or therapy resistance in the near future. This review will provide a novel insight to understanding the paradoxical roles of autophagy in tumor suppression and tumor promotion.

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“…9-ING-41, for instance, is a malmeimide-derived GSK3 inhibitor that initially showed potent anti-proliferative activity [203] and capacity to overcome chemoresistance [204] in different cancer cell lines. At the moment, the safety and efficacy of 9-ING-41 are being addressed in patients with hematologic malignancies and solid tumors in a phase I/II study (NCT03678883) [197,205].…”

Section: Clinical Application Of Gsk3 Inhibitorsmentioning

confidence: 99%

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Hoffmeister

Diekmann

Brand

et al. 2020

Cells

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GSK3 has been implicated for years in the regulation of inflammation and addressed in a plethora of scientific reports using a variety of experimental (disease) models and approaches. However, the specific role of GSK3 in the inflammatory process is still not fully understood and controversially discussed. Following a detailed overview of structure, function, and various regulatory levels, this review focusses on the immunoregulatory functions of GSK3, including the current knowledge obtained from animal models. Its impact on pro-inflammatory cytokine/chemokine profiles, bacterial/viral infections, and the modulation of associated pro-inflammatory transcriptional and signaling pathways is discussed. Moreover, GSK3 contributes to the resolution of inflammation on multiple levels, e.g., via the regulation of pro-resolving mediators, the clearance of apoptotic immune cells, and tissue repair processes. The influence of GSK3 on the development of different forms of stimulation tolerance is also addressed. Collectively, the role of GSK3 as a kinase balancing the initiation/perpetuation and the amelioration/resolution of inflammation is highlighted.

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9-ING-41, a small molecule inhibitor of GSK-3beta, potentiates the effects of anticancer therapeutics in bladder cancer

Cited by 37 publications

References 34 publications

GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals

GSK-3β Can Regulate the Sensitivity of MIA-PaCa-2 Pancreatic and MCF-7 Breast Cancer Cells to Chemotherapeutic Drugs, Targeted Therapeutics and Nutraceuticals

Contrast effects of autophagy in the treatment of bladder cancer

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

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