bims-istrec Biomed News
on Integrated stress response in cancer
Issue of 2021–12–12
two papers selected by
the Vincenzo Ciminale lab, Istituto Oncologico Veneto
  1. Induction of Apoptosis in Human Pancreatic Cancer Stem Cells by the Endoplasmic Reticulum-Targeted Alkylphospholipid Analog Edelfosine and Potentiation by Autophagy Inhibition.
  2. Highly potent dopamine receptor D2 antagonist ONC206 demonstrates anti-tumorigenic activity in endometrial cancer.
  1. Cancers (Basel). 2021 Dec 05. pii: 6124. [Epub ahead of print]13(23):
    Induction of Apoptosis in Human Pancreatic Cancer Stem Cells by the Endoplasmic Reticulum-Targeted Alkylphospholipid Analog Edelfosine and Potentiation by Autophagy Inhibition.
    Consuelo Gajate, Odile Gayet, Nicolas A Fraunhoffer, Juan Iovanna, Nelson Dusetti, Faustino Mollinedo.
      Pancreatic cancer is one of the most lethal malignancies with a poor and gloomy prognosis and the highest mortality-to-incidence ratio. Pancreatic cancer remains an incurable malignancy, and current therapies are ineffective. We isolated cancer stem cells (CSCs) from the human PANC-1 pancreatic cancer cell line as CD44+CD24+EpCAM+ cells. These CSCs form pancreatic cancer spheres or spheroids and develop tumors in SCID mice after subcutaneous injection of as few as 100 cells per mouse. Here, we found that the alkylphospholipid analog edelfosine inhibited CSC pancreatic cancer spheroid formation and induced cell death, as assessed by an increase in the percentage of cells in the sub-G0/G1 region by means of flow cytometry, indicative of DNA breakdown and apoptosis. This correlated with an increase in caspase-3 activity and PARP breakdown, as a major substrate of caspase-3, following PANC-1 CSC treatment with edelfosine. The antitumor ether lipid edelfosine colocalized with the endoplasmic reticulum in both PANC-1 cells as well as PANC-1 CSCs by using a fluorescent edelfosine analog, and induced an endoplasmic reticulum stress response in both PANC-1 cells and PANC-1 CSCs, with a potent CHOP/GADD153 upregulation. Edelfosine elicited a strong autophagy response in both PANC-1 cells and PANC-1 CSCs, and preincubation of CSCs with autophagy inhibitors, chloroquine or bafilomycin A1, enhanced edelfosine-induced apoptosis. Primary cultures from pancreatic cancer patients were sensitive to edelfosine, as well as their respective isolated CSCs. Nontumorigenic pancreatic human cell line HPNE and normal human fibroblasts were largely spared. These data suggest that pancreatic CSCs isolated from established cell lines and pancreatic cancer patients are sensitive to edelfosine through its accumulation in the endoplasmic reticulum and induction of endoplasmic reticulum stress.
    Keywords:  alkylphospholipid analog; antitumor ether lipid; autophagy; edelfosine; endoplasmic reticulum; endoplasmic reticulum targeting; pancreatic cancer; pancreatic cancer spheroid; pancreatic cancer stem cell; primary cultures from pancreatic cancer patients
    DOI:  https://doi.org/10.3390/cancers13236124
  2. Am J Cancer Res. 2021 ;11(11): 5374-5387
    Highly potent dopamine receptor D2 antagonist ONC206 demonstrates anti-tumorigenic activity in endometrial cancer.
    Allison Staley, Katherine Tucker, Yajie Yin, Xin Zhang, Yali Fan, Yingao Zhang, Ziwei Fang, Wenchuan Sun, Hongyan Suo, Xiaoling Zhao, Ziyi Zhao, Varun Vijay Prabhu, Joshua E Allen, Chunxiao Zhou, Victoria L Bae-Jump.
      Endometrial cancer (EC) is a highly obesity-driven cancer, with limited treatment options. ONC201 is an imipridone that selectively antagonizes the G protein-coupled receptors dopamine receptor D2 and D3 (DRD2/3) and activates human mitochondrial caseinolytic protease P (ClpP). It is a promising first-in-class small molecule that has been reported to have anti-neoplastic activity in various types of cancer through induction of the integrated stress response (ISR) as well as through stimulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and subsequent induction of apoptosis. ONC201 is being evaluated in Phase II clinical trials for solid tumors and hematological malignancies, including EC. ONC206 is an analog of ONC201 with nanomolar potency in Phase I clinical trials. This study evaluated the anti-tumor efficacy of ONC206 in EC cell lines and the Lkb1fl/flp53fl/fl genetically engineered mouse model of endometrioid EC. ONC206 revealed greater potency than ONC201 in the inhibition of proliferation in EC cell lines, with IC50 concentration ranges of 0.21-0.32 µM for ONC026 versus 2.14-3.53 µM for ONC201. ONC206 induced cellular stress, apoptosis and cell cycle G1 arrest, accompanied by inhibition of the AKT/mTOR/S6 pathways in EC cells. Diet-induced obesity accelerated tumor growth in Lkb1fl/flp53fl/fl mice. ONC206 inhibited EC tumor size and weight in both obese and lean mice after 4 weeks of treatment. Treatment with ONC206 led to a decrease in expression of Ki67, BCL-XL and phosphorylation of S6, as well as an increase in ClpP in endometrial tumors under both obese and lean conditions. Overall, the pre-clinical efficacy of ONC206 is promising and worthy of further exploration in clinical trials for endometrioid EC.
    Keywords:  ONC206; apoptosis; dopamine receptors; endometrial cancer; obesity
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