Hsp90 inhibitors deplete key anti-apoptotic proteins in pediatric solid tumor cells and demonstrate synergistic anticancer activity with cisplatin

10556 Background: Ewing sarcoma (EWS) expresses high levels of Schlafen-11 (SLFN11). SLFN11 disrupts checkpoint maintenance and may serve as a biomarker to assess sensitivity to Poly (ADP-ribose) polymerase 1 and 2 inhibitors (PARPi). The goal of this study is to evaluate SLFN11 protein expression in a panel of pediatric solid tumors and correlate levels of protein with sensitivity to PARP inhibition combined with ionizing radiation (IR), a component of therapy for many pediatric solid tumors and a potent inducer of DNA damage. Methods: SLFN11 mRNA and protein levels were assessed by quantitative RT-PCR, and immunohistochemistry, Western blot, and immunofluorescence microscopy, respectively. PARPi included: talazoparib (TAL), niraparib (NIR), veliparib (VEL), and olaparib (OLA). Approximately 30 minutes after addition of systemic therapy, graded doses of radiation were delivered and viability across a panel of pediatric solid tumor cell lines was measured using the ATP-based Cell TiterGlo assay and confirmed with the colony formation assay. Results: We found that SLFN11 mRNA and protein is expressed at high levels in EWS, and SLFN11 is also variably present in a subset of other pediatric solid tumor lines, including desmoplastic small round cell tumor, osteosarcoma, and rhabdomyosarcoma. In all tumor cells with detectable SLFN11 expression, viability was reduced by greater than 90% when exposed to 2Gy IR and 1-10nM TAL, whereas cells with undetectable levels of SLFN11 were 5-10 times less sensitive. Intriguingly, variation in the potentiation between specific PARPi and IR correlated with the ability to form drug-induced PARP-DNA adducts, with the strong PARP trapper TAL showing ~10-fold higher potency compared to the moderate trapper NIR, and ~300-fold more potency relative to the weak trapper VEL. Consistent with our PARPi findings, the toposiomerase 1 inhibitor irinotecan, which also forms DNA adducts, potentiated with IR similarly to TAL at concentrations < 10nM in tumor cells expressing detectable levels of SLFN11. Conclusions: SLFN11 is present in select pediatric solid tumors and may induce a DNA repair defect that is best exploited by combining low-doses of TAL and irinotecan with IR.

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Dimers of Melampomagnolide B Exhibit Potent Anticancer Activity against Hematological and Solid Tumor Cells

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.5b01187 ◽

2015 ◽

Vol 58 (22) ◽

pp. 8896-8906 ◽

Cited By ~ 13

Author(s):

Venumadhav Janganati ◽

Jessica Ponder ◽

Craig T. Jordan ◽

Michael J. Borrelli ◽

Narsimha Reddy Penthala ◽

...

Keyword(s):

Anticancer Activity ◽

Tumor Cells ◽

Solid Tumor

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Arginine modification of lycosin-I to improve inhibitory activity against cancer cells

Organic & Biomolecular Chemistry ◽

10.1039/c7ob02233f ◽

2017 ◽

Vol 15 (44) ◽

pp. 9379-9388 ◽

Cited By ~ 8

Author(s):

Peng Zhang ◽

Jing Ma ◽

Yujie Yan ◽

Bo Chen ◽

Bobo Liu ◽

...

Keyword(s):

Physicochemical Properties ◽

Anticancer Activity ◽

Cancer Cells ◽

Tumor Cells ◽

Solid Tumor ◽

Inhibitory Activity ◽

High Serum ◽

Serum Stability ◽

Arginine Modification

Herein, arginine modification rendered Lycosin-I with higher anticancer activity, penetrability, and dissemination ability against solid tumor cells due to the optimized physicochemical properties and high serum stability.

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Anticancer Activity of Diosgenin and its Semi-synthetic Derivatives: Role in Autophagy Mediated Cell Death and Induction of Apoptosis

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521666210105111224 ◽

2021 ◽

Vol 21 ◽

Author(s):

Nivedita Bhardwaj ◽

Nancy Tripathi ◽

Bharat Goel ◽

Shreyans K. Jain

Keyword(s):

Cell Death ◽

Cancer Treatment ◽

Anticancer Activity ◽

Tumor Cells ◽

Cancer Progression ◽

Rational Approach ◽

Potential Candidate ◽

Potential Implication ◽

Apoptosis Protein ◽

Synthetic Derivatives

: During cancer progression, the unrestricted proliferation of cells is supported by the impaired cell death response provoked by certain oncogenes. Both autophagy and apoptosis are the signaling pathways of cell death, which are targeted for cancer treatment. Defects in apoptosis result in reduced cell death and ultimately tumor progression. The tumor cells lacking apoptosis phenomena are killed by ROS- mediated autophagy. The autophagic programmed cell death requires apoptosis protein for inhibiting tumor growth; thus, the interconnection between these two pathways determines the fate of a cell. The cross-regulation of autophagy and apoptosis is an important aspect to modulate autophagy, apoptosis and to sensibilise apoptosis-resistant tumor cells under metabolic stress and might be a rational approach for drug designing strategy for the treatment of cancer. Numerous proteins involved in autophagy have been investigated as the druggable target for anticancer therapy. Several compounds of natural origin have been reported, to control autophagy activity through the PI3K/Akt/mTOR key pathway. Diosgenin, a steroidal sapogenin has emerged as a potential candidate for cancer treatment. It induces ROS-mediated autophagy, inhibits PI3K/Akt/mTOR pathway, and produces cytotoxicity selectively in cancer cells. This review aims to focus on optimal strategies using diosgenin to induce apoptosis by modulating the pathways involved in autophagy regulation and its potential implication in the treatment of various cancer. The discussion has been extended to the medicinal chemistry of semi-synthetic derivatives of diosgenin exhibiting anticancer activity.

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Primary pancreatic glomus tumor invading into the superior mesenteric vein: a case report

Surgical Case Reports ◽

10.1186/s40792-020-01058-7 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Ichiro Tamaki ◽

Yohei Hosoda ◽

Hironobu Sasano ◽

Yu Sasaki ◽

Hidenori Kiyochi ◽

...

Keyword(s):

Case Report ◽

Tumor Cells ◽

Solid Tumor ◽

Superior Mesenteric Vein ◽

Glomus Tumor ◽

Small Cells ◽

Histopathological Analysis ◽

Glomus Tumors ◽

Mesenteric Vein ◽

Direct Invasion

Abstract Background Glomus tumors are subcutaneous tumors arising from glomus bodies, thermoregulatory components of the skin. These tumors could occur in visceral organs where glomus bodies are not normally present. Herein, we report a case of primary pancreatic glomus tumor with aggressive direct invasion into the superior mesenteric vein (SMV). To the best of our knowledge, this is the second case report of a glomus tumor arising in the pancreas. Case presentation A 46-year-old woman was referred to our hospital due to vomiting with epigastric and back pain. Dynamic-CT revealed a well-circumscribed hypervascular mass, measuring 37 mm in its maximal diameter involving the pancreatic head. Both CT and endoscopic ultrasonography (EUS) revealed direct invasion into the SMV and radiologically suspected tumor thrombus. Biopsy sample obtained by EUS-guided fine needle aspiration revealed proliferation of small cells, round-to-oval tumor cells with round nuclei and scant cytoplasm. A histological diagnosis of pancreatic neuroendocrine tumor, G1 was initially considered. Therefore, subtotal stomach-preserving pancreatoduodenectomy using Child-II reconstruction was subsequently performed. Her SMV was resected and reconstructed due to extensive tumor involvement. Subsequent histopathological analysis revealed solid tumor cells proliferation that comprised oval-shaped nuclei and scant cytoplasm around disorganized or slit-shaped vessels in hematoxylin–eosin-stained slides. Immunohistochemical analysis then demonstrated positive immunoreactivity for smooth muscle actin, vimentin, and CD34, but negative for chromogranin A, synaptophysin, CD56, and signal transducer and activator of transcription 6. Based on these histological findings of resected specimens, the lesion was subsequently diagnosed as a primary pancreatic glomus tumor harboring direct invasion into the SMV. Her postoperative course was uneventful and annual surveys for the following 4 years post-op detected no clinical signs of recurrence. Conclusions We report a very rare case of glomus tumor of the pancreas accompanied by venous invasion. Curative surgical resection is the best treatment option for pancreatic glomus tumors. Although pancreatic glomus tumor is rare, it should be taken into consideration in the differential diagnosis of a pancreatic solid tumor with hypervascularity.

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Enhanced antitumor activity of irofulven in combination with irinotecan in pediatric solid tumor xenograft models

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-004-0902-2 ◽

2004 ◽

Vol 55 (5) ◽

pp. 411-419 ◽

Cited By ~ 17

Author(s):

Michael H. Woo ◽

Jennifer K. Peterson ◽

Catherine Billups ◽

Hua Liang ◽

Mary-Ann Bjornsti ◽

...

Keyword(s):

Antitumor Activity ◽

Solid Tumor ◽

Tumor Xenograft ◽

Pediatric Solid Tumor ◽

Xenograft Models

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163 Improved anti-tumor activity of next-generation TCR-engineered T cells through CD8 co-expression

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.163 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A173-A173

Author(s):

Gagan Bajwa ◽

Justin Gunesch ◽

Inbar Azoulay-Alfaguter ◽

Melinda Mata ◽

Ali Mohamed ◽

...

Keyword(s):

T Cells ◽

Tumor Cells ◽

Solid Tumor ◽

Cd4 T Cells ◽

Tumor Response ◽

Hla Class I ◽

Next Generation ◽

Engineered T Cells ◽

Anti Tumor Activity

BackgroundSuccessful targeting of solid tumors with TCR-engineered T cells (TCR-T) will require eliciting of antigen-specific, multi-dimensional, sustained anti-tumor immune response by infused T cells while overcoming the suppressive tumor microenvironment. First-generation TCR-T approaches have demonstrated clinical efficacy in some solid cancers. However, effective treatment across several solid tumor indications may require engineered T cells with enhanced anti-tumor activity. Here, we show pre-clinical data from one of the engineering approaches currently being developed for next-generation ACTengine® TCR-T product candidates. We evaluated the impact of co-expression of different CD8 co-receptors on functionality of CD4+ and CD8+ T cells genetically modified with an HLA class I-restricted TCR and determined the depth and durability of anti-tumor response in vitro.MethodsHere, we used a PRAME-specific TCR currently being tested in the ACTengine® IMA203 clinical trial. T cells expressing either the TCR alone or co-expressing the TCR and CD8α homodimer (TCR.CD8α) or CD8αβ heterodimer (TCR.CD8αβ) were characterized for transgene expression, antigen-recognition, and functional efficacy in vitro. Comprehensive evaluation of CD4+ T cells expressing TCR.CD8α or TCR.CD8αβ was performed focusing on cytotoxic potential and the breadth of cytokine response against target-positive tumor cell lines.ResultsIntroduction of CD8α or CD8αβ enabled detection of transgenic TCR on the surface of CD4+ T cells via HLA multimer-guided flow cytometry otherwise lacking in the TCR only transduced T cells. Co-expression of either form of CD8 co-receptor endowed CD4+ T cells with the ability to recognize and kill target positive tumor cells; however, genetic modification with TCR.CD8αβ led to more pronounced CD4+ T cell activation as compared to TCR.CD8α. Most distinct differences were observed in the breadth and magnitude of cytokine responses, less in cytotoxic activity against tumor cells. T cells expressing TCR.CD8αβ showed superior induction of Th1 cytokines e.g. IFNγ, TNFα, IL-2, GM-CSF in vitro upon antigen stimulation as compared to TCR.CD8α-T cells. Additionally, TCR.CD8αβ T cells demonstrated more efficient engagement with antigen-presenting cells and consequently, modulation of cytokine response than TCR.CD8α-T cells.ConclusionsOur findings illustrate that engaging CD4+ T cells via CD8 co-expression potentiates anti-tumor activity of HLA class I restricted TCR-T cells in vitro. The pleiotropic effects mediated by activated CD4+ T cells including acquired cytotoxicity may potentially improve outcomes in solid tumor patients when applied clinically. In addition, the differential functional profile of TCR-T cells co-expressing either CD8α or CD8αβ suggests that optimizing the type of co-receptor is relevant to maximize anti-tumor response.

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Antitumor activity of L-asparaginase from Erwinia Carotovora from against different leukemic and solid tumours cell lines

Biomeditsinskaya Khimiya ◽

10.18097/pbmc20135905498 ◽

2013 ◽

Vol 59 (5) ◽

pp. 498-513 ◽

Cited By ~ 9

Author(s):

O.Yu. Abakumova ◽

O.V. Podobed ◽

P.A. Karalkin ◽

L.I. Kondakova ◽

N.N. Sokolov

Keyword(s):

Dna Synthesis ◽

Tumor Cells ◽

Solid Tumor ◽

Human Fibroblasts ◽

Erwinia Carotovora ◽

Cell Number ◽

Jurkat Cells ◽

Leukemic Cells ◽

Cycle Phase ◽

Tumor Cell Death

We have studied dose- and time-dependent antitumor and cytotoxic effects of Erwinia carotovora L-asparaginase (ECAR LANS) and Escherichia coli L-asparaginase (MEDAC) on human leukemic cells and human and animal solid tumor cells. We determined the sensitivity of tumor cells to L-asparaginases, as well the effect L-asparaginases on cell growth rate, protein and DNA synthesis per se and with addition of different cytostatics. The data obtained demonstrated that ECAR LANS L-asparaginase suppressed growth of all tested solid tumor cells. Evaluation of leukemic cell number after treatment with L-asparaginases for 24, 48 and 72 h demonstrated that asparagine deficiency did not kill cells but stopped normal cell division and had no effect on protein and DNA synthesis. Cytofluorometric study of solid and leukemic cells demonstrated that the treatment with L-asparaginase for 72 h did not change cell cycle phase distribution and did not increase the number of apoptotic cells. The HL-60 cell line was only exemption. At the same time, cells treatment with L-asparaginase and doxorubicin combination leaded to increase of apoptotypical cell number to 60% for MCF7 cells, to 40% for Jurkat cells and to 99% for HL-60 cells. We have excluded apoptosis as main reason for tumor cell death after asparaginase treatment because multi resistant Jurkat/A4 cells have been asparaginase sensitive. We have not found ECAR LANS L-asparaginase effect on normal human fibroblasts growth ability and we had come to conclusion that enzyme cytotoxcisity related only with asparagine deficiency.

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