GSK3β as a novel promising target to overcome chemoresistance in pancreatic cancer

Pecoraro, Camilla; Faggion, Beatrice; Balboni, Beatrice; Carbone, Daniela; Peters, Godefridus J.; Diana, Patrizia; Assaraf, Yehuda G.; Giovannetti, Elisa

doi:10.1016/j.drup.2021.100779

Cited by 48 publications

(29 citation statements)

References 153 publications

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“…Palliative treatment options for non-resectable PDAC include chemotherapy (gemcitabine, oxaliplatin, cisplatin, 5-FU, and taxanes), with the standard treatment for locally advanced PDAC being chemotherapy (FOLFIRINOX or Gem/Abraxane) with or without radiation [ 2 ], despite the significant complications [ 4 ]. Additionally, a number of small molecule kinase inhibitors (including Erlotnib, Sunitinib, and others) have also been approved for treating PaCa [ 5 , 6 , 7 , 8 ]. Thermal ablation, including radiofrequency ablation (RFA), microwave, high-intensity focused ultrasound (HIFU), and cryoablation (CA), are now being explored as treatment options for non-resectable PaCa [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

An In Vitro Investigation into Cryoablation and Adjunctive Cryoablation/Chemotherapy Combination Therapy for the Treatment of Pancreatic Cancer Using the PANC-1 Cell Line

et al. 2022

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As the incidence of pancreatic ductal adenocarcinoma (PDAC) continues to grow, so does the need for new strategies for treatment. One such area being evaluated is cryoablation. While promising, studies remain limited and questions surrounding basic dosing (minimal lethal temperature) coupled with technological issues associated with accessing PDAC tumors and tumor proximity to vasculature and bile ducts, among others, have limited the use of cryoablation. Additionally, as chemotherapy remains the first-line of attack for PDAC, there is limited information on the impact of combining freezing with chemotherapy. As such, this study investigated the in vitro response of a PDAC cell line to freezing, chemotherapy, and the combination of chemotherapy pre-treatment and freezing. PANC-1 cells and PANC-1 tumor models were exposed to cryoablation (freezing insult) and compared to non-frozen controls. Additionally, PANC-1 cells were exposed to varying sub-clinical doses of gemcitabine or oxaliplatin alone and in combination with freezing. The results show that freezing to −10 °C did not affect viability, whereas −15 °C and −20 °C resulted in a reduction in 1 day post-freeze viability to 85% and 20%, respectively, though both recovered to controls by day 7. A complete cell loss was found following a single freeze below −25 °C. The combination of 100 nM gemcitabine (1.1 mg/m2) pre-treatment and a single freeze at −15 °C resulted in near-complete cell death (<5% survival) over the 7-day assessment interval. The combination of 8.8 µM oxaliplatin (130 mg/m2) pre-treatment and a single −15 °C freeze resulted in a similar trend of increased PANC-1 cell death. In summary, these in vitro results suggest that freezing alone to temperatures in the range of −25 °C results in a high degree of PDAC destruction. Further, the data support a potential combinatorial chemo/cryo-therapeutic strategy for the treatment of PDAC. These results suggest that a reduction in chemotherapeutic dose may be possible when offered in combination with freezing for the treatment of PDAC.

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Section: Introductionmentioning

confidence: 99%

An In Vitro Investigation into Cryoablation and Adjunctive Cryoablation/Chemotherapy Combination Therapy for the Treatment of Pancreatic Cancer Using the PANC-1 Cell Line

et al. 2022

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“…GSK-3 beta has been previously identified as a potential therapeutic target in several difficult to treat cancers including pancreatic cancer and GBM [ 7 , 8 , 9 ]. It is known to have tissue specific functions and is particularly abundant in the brain during development with a pronounced neuronal localization.…”

Section: Introductionmentioning

confidence: 99%

GSK-3 Inhibition Is Cytotoxic in Glioma Stem Cells through Centrosome Destabilization and Enhances the Effect of Radiotherapy in Orthotopic Models

Brüning-Richardson

Shaw

Tams

et al. 2021

Cancers

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Background: Previous data on glycogen synthase kinase 3 (GSK-3) inhibition in cancer models support a cytotoxic effect with selectivity for tumor cells compared to normal tissue but the effect of these inhibitors in glioma has not been widely studied. Here, we investigate their potential as cytotoxics in glioma. Methods: We assessed the effect of pharmacologic GSK-3 inhibition on established (U87, U251) and patient-derived (GBM1, GBM4) glioblastoma (GBM) cell lines using cytotoxicity assays as well as undertaking a detailed investigation of the effect on cell cycle, mitosis, and centrosome biology. We also assessed drug uptake and efficacy of GSK-3 inhibition alone and in combination with radiation in xenograft models. Results: Using the selective GSK-3 inhibitor AZD2858, we demonstrated single agent cytotoxicity in two patient-derived glioma cell lines (GBM1, GBM4) and two established cell lines (U251 and U87) with IC50 in the low micromolar range promoting centrosome disruption, failed mitosis, and S-phase arrest. Glioma xenografts exposed to AZD2858 also showed growth delay compared to untreated controls. Combined treatment with radiation increased the cytotoxic effect of clinical radiation doses in vitro and in orthotopic glioma xenografts. Conclusions: These data suggest that GSK-3 inhibition promotes cell death in glioma through disrupting centrosome function and promoting mitotic failure and that AZD2858 is an effective adjuvant to radiation at clinical doses.

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“…Although GSK-3β depletion had little effect on viability of p53-null HCT116p53KO colon cancer cells and p53-mut HT1376 bladder cancer cells, it restored the sensitivity of these cells to DNA-damaging agents, such as 5-FU. GSK-3β is described to be a positive regulator of NF-κB–mediated chemoresistance of cancer cells ( Pecoraro et al, 2021 ). Therefore, mechanistically, inhibition or depletion of GSK-3β bypasses NF-κB–mediated drug resistance.…”

Section: Discussionmentioning

confidence: 99%

“…They have approximately 100 known targets and are involved in regulating normal cellular homeostasis and also tumor development, progression, and metastasis ( Cormier and Woodgett, 2017 ). It was GSK-3β in the focus of the majority of the studies in the oncology field due to its known effects on many pathological processes ( Pecoraro et al, 2021 ). GSK-3β regulates many biological pathways, including cyclic adenosine monophosphate (cAMP) signaling, Wnt, Hedgehog, Notch, transforming growth factor-beta (TGF-β), nuclear factor of activated T cells (NF-AT), and the agonists that act via stimulation of phosphatidylinositol 3-kinase (PI3K) ( Cormier and Woodgett, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells

et al. 2021

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Colorectal cancer (CRC) is one of the most common and lethal types of cancer. Although researchers have made significant efforts to study the mechanisms underlying CRC drug resistance, our knowledge of this disease is still limited, and novel therapies are in high demand. It is urgent to find new targeted therapy considering limited chemotherapy options. KRAS mutations are the most frequent molecular alterations in CRC. However, there are no approved K-Ras targeted therapies for these tumors yet. GSK-3β is demonstrated to be a critically important kinase for the survival and proliferation of K-Ras–dependent pancreatic cancer cells. In this study, we tested combinations of standard-of-care therapy and 9-ING-41, a small molecule inhibitor of GSK-3β, in CRC cell lines and patient-derived tumor organoid models of CRC. We demonstrate that 9-ING-41 inhibits the growth of CRC cells via a distinct from chemotherapy mechanism of action. Although molecular biomarkers of 9-ING-41 efficacy are yet to be identified, the addition of 9-ING-41 to the standard-of-care drugs 5-FU and oxaliplatin could significantly enhance growth inhibition in certain CRC cells. The results of the transcriptomic analysis support our findings of cell cycle arrest and DNA repair deficiency in 9-ING-41–treated CRC cells. Notably, we find substantial similarity in the changes of the transcriptomic profile after inhibition of GSK-3β and suppression of STK33, another critically important kinase for K-Ras–dependent cells, which could be an interesting point for future research. Overall, the results of this study provide a rationale for the further investigation of GSK-3 inhibitors in combination with standard-of-care treatment of CRC.

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GSK3β as a novel promising target to overcome chemoresistance in pancreatic cancer

Cited by 48 publications

References 153 publications

An In Vitro Investigation into Cryoablation and Adjunctive Cryoablation/Chemotherapy Combination Therapy for the Treatment of Pancreatic Cancer Using the PANC-1 Cell Line

An In Vitro Investigation into Cryoablation and Adjunctive Cryoablation/Chemotherapy Combination Therapy for the Treatment of Pancreatic Cancer Using the PANC-1 Cell Line

GSK-3 Inhibition Is Cytotoxic in Glioma Stem Cells through Centrosome Destabilization and Enhances the Effect of Radiotherapy in Orthotopic Models

9-ING-41, a Small Molecule Inhibitor of GSK-3β, Potentiates the Effects of Chemotherapy on Colorectal Cancer Cells

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