Combination treatment of resveratrol and capsaicin radiosensitizes pancreatic tumor cells by unbalancing DNA repair response to radiotherapy towards cell death

e14635 Background: Lenalidomide is an immunomodulatory and anti-angiogenic agent that has demonstrated activity against a range of hematological malignancies. Despite evidence of direct anti-proliferative activity against hematological cells in vitro, there is no evidence of single agent direct activity against solid tumor cells in vitro. To take advantage of its known immune-enhancing properties alongside direct anti-tumor agents, lenalidomide is being advanced in solid tumor indications in combination with other agents. There are few data regarding the combination of lenalidomide and standard of care chemotherapeutic agents, such as gemcitabine. Methods: Here, we assess the effects of lenalidomide alone, and in combination with gemcitabine, on pancreatic cancer cell growth and survival, and the ability of lenalidomide to enhance the ability of human PBMC to kill allogeneic pancreatic tumor cells (BxPC3, PANC-1 and MiaPaCa) in a PBMC:tumor cell co-culture model. Results: Lenalidomide alone had no effect on the proliferation of pancreatic cancer cells (BxPC-3 and Panc-1) whereas gemcitabine had moderate anti-proliferative activity. With combination therapy there was clear synergistic enhancement of anti-proliferative activity in both cell lines and additive effects were observed in a BxPC-3 xenograft mouse model of pancreatic cancer. About 20% of tumor cells were sensitive to immune-mediated cell death and, for BxPC3, this was increased significantly in the presence of lenalidomide. Lenalidomide significantly and dose-dependently enhanced immune-mediated killing (both T and NK cells are required for tumor cell killing in this model). For PANC-1 and MiaPaCa, immune-mediated killing was also increased by lenalidomide, albeit non-significantly. Conclusions: These results suggest that, in addition to anti-angiogenic and other effects within the tumor microenvironment, lenalidomide may act as an immune adjuvant to enhance the recognition and apoptosis of tumor cells by host T and NK cells. These studies support the potential utility of lenalidomide in combination with chemotherapeutic agents, gemcitabine in particular, in the treatment of patients with solid tumors including pancreatic cancer. [Table: see text]

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Metabolism-based GP-2250 in combination with gemcitabine as a novel approach to pancreatic cancer: A mouse xenograft study.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16750 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16750-e16750

Author(s):

Chris Braumann ◽

Marie Buchholz ◽

Britta Majchrzak - Stiller ◽

Stephan Hahn ◽

Waldemar Uhl ◽

...

Keyword(s):

Pancreatic Cancer ◽

Clinical Trial ◽

Tumor Growth ◽

Tumor Cell ◽

Tumor Cells ◽

Cell Lines ◽

Combination Treatment ◽

Cancer Metabolism ◽

Pancreatic Tumor ◽

Tumor Cell Lines

e16750 Background: GP-2250, a novel oxathiazine derivative, displayed apoptotic cytotoxicity against various tumor cell lines but not normal cells. It was therefore tested whether its antineoplastic potential - alone or in combination – could be leveraged specifically against pancreatic cancer. Methods: GP-2250 is a cancer metabolism-based therapeutic. It depleted metabolic energy through inhibition of the enzyme GAPDH (glyceraldehyde-3-phosphate dehydrogenase) which is rate limiting for aerobic glycolysis. ATP was decreased in a time- and dose-dependent manner in pancreatic tumor cell lines and ROS was increased. Mitochondrial dysfunction was triggered by an increased expression of Bax and decreased expression of Bcl2, leading to apoptosis. Cytotoxicity of GP-2250 was ROS-dependent. It was blocked by N-acetylcysteine. Results: GP-2250 substantially increased the sensitivity of pancreatic tumor cells to various chemotherapeutics in particular to gemcitabine (Gem). At doses which were inactive or barely active per se, the combination of GP-2250 and Gem caused striking cytotoxicity in patient-derived primary tumor cells in vitro, pointing to a strong synergy between the two agents. This finding was substantiated in vivo by patient-derived xenograft (PDX) studies in nude mice. While GP-2250 and Gem, given as monotherapy (500 mg/kg and 50 mg/kg respectively, 2x/week), showed only a limited antineoplastic response, the combination treatment resulted in a significantly higher anti-tumor activity as shown in further PDX. Tumor regression was found in 5 out of 9 PDX based on RECIST criteria. Stable disease was reached in 3 of the remaining grafts. In 1 xenograft, which was unresponsive to Gem, the combination treatment nevertheless achieved a reduction in tumor growth which significantly exceeded that of GP-2250 monotherapy. Conclusions: GP-2250 is a novel cancer metabolism-based therapeutic. GP-2250, in combination with Gem, strongly reduces tumor growth in patient-derived xenografts exceeding by far the response to monotherapy. GP-2250 is being evaluated in a Phase I clinical trial in patients diagnosed with advanced pancreatic cancer (Clinical Trial NCT03854110).

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Autophagic Cell Death of Human Pancreatic Tumor Cells Mediated by Oleandrin, a Lipid-Soluble Cardiac Glycoside

Integrative Cancer Therapies ◽

10.1177/1534735407309623 ◽

2007 ◽

Vol 6 (4) ◽

pp. 354-364 ◽

Cited By ~ 81

Author(s):

Robert A. Newman ◽

Yasuko Kondo ◽

Tomohisa Yokoyama ◽

Susan Dixon ◽

Carrie Cartwright ◽

...

Keyword(s):

Cell Death ◽

Tumor Cells ◽

Cardiac Glycoside ◽

Pancreatic Tumor ◽

Autophagic Cell Death

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Shikonin induces immunogenic cell death in tumor cells and enhances dendritic cell-based cancer vaccine

Planta Medica ◽

10.1055/s-0032-1320648 ◽

2012 ◽

Vol 78 (11) ◽

Cited By ~ 1

Author(s):

HM Chen ◽

PH Wang ◽

SS Chen ◽

CC Wen ◽

YH Chen ◽

...

Keyword(s):

Cell Death ◽

Dendritic Cell ◽

Tumor Cells ◽

Cancer Vaccine ◽

Immunogenic Cell Death

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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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Discovery of pyrano[2,3-d]pyrimidine-2,4-dione derivatives as novel PARP-1 inhibitors: design, synthesis and antitumor activity

RSC Advances ◽

10.1039/d0ra10321g ◽

2021 ◽

Vol 11 (8) ◽

pp. 4454-4464

Author(s):

Nour E. A. Abd El-sattar ◽

Eman H. K. Badawy ◽

Eman Z. Elrazaz ◽

Nasser S. M. Ismail

Keyword(s):

Cell Death ◽

Dna Repair ◽

Antitumor Activity ◽

Cancer Cell ◽

Cytotoxic Agents ◽

Repair Mechanism ◽

Design Synthesis ◽

Parp 1

PARP-1 are involved in DNA repair damage and so PARP-1 inhibitors have been used as potentiators in combination with DNA damaging cytotoxic agents to compromise the cancer cell DNA repair mechanism, resulting in genomic dysfunction and cell death.

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Damage-Associated Molecular Patterns Modulation by microRNA: Relevance on Immunogenic Cell Death and Cancer Treatment Outcome

Cancers ◽

10.3390/cancers13112566 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2566

Author(s):

María Julia Lamberti ◽

Annunziata Nigro ◽

Vincenzo Casolaro ◽

Natalia Belén Rumie Vittar ◽

Jessica Dal Col

Keyword(s):

Cell Death ◽

Tumor Cells ◽

Cell Activation ◽

Adaptive Immune Response ◽

Current Status ◽

Immunogenic Cell Death ◽

Basal Expression ◽

Antigen Presenting ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns

Immunogenic cell death (ICD) in cancer is a functionally unique regulated form of stress-mediated cell death that activates both the innate and adaptive immune response against tumor cells. ICD makes dying cancer cells immunogenic by improving both antigenicity and adjuvanticity. The latter relies on the spatiotemporally coordinated release or exposure of danger signals (DAMPs) that drive robust antigen-presenting cell activation. The expression of DAMPs is often constitutive in tumor cells, but it is the initiating stressor, called ICD-inducer, which finally triggers the intracellular response that determines the kinetics and intensity of their release. However, the contribution of cell-autonomous features, such as the epigenetic background, to the development of ICD has not been addressed in sufficient depth. In this context, it has been revealed that several microRNAs (miRNAs), besides acting as tumor promoters or suppressors, can control the ICD-associated exposure of some DAMPs and their basal expression in cancer. Here, we provide a general overview of the dysregulation of cancer-associated miRNAs whose targets are DAMPs, through which new molecular mediators that underlie the immunogenicity of ICD were identified. The current status of miRNA-targeted therapeutics combined with ICD inducers is discussed. A solid comprehension of these processes will provide a framework to evaluate miRNA targets for cancer immunotherapy.

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Gene-Directed Enzyme Prodrug Therapy by Dendrimer-Like Mesoporous Silica Nanoparticles against Tumor Cells

Nanomaterials ◽

10.3390/nano11051298 ◽

2021 ◽

Vol 11 (5) ◽

pp. 1298

Author(s):

Vicente Candela-Noguera ◽

Gema Vivo-Llorca ◽

Borja Díaz de Greñu ◽

María Alfonso ◽

Elena Aznar ◽

...

Keyword(s):

Cell Death ◽

Mesoporous Silica ◽

Silica Nanoparticles ◽

Tumor Cells ◽

Mesoporous Silica Nanoparticles ◽

Combined Treatment ◽

Bond Rupture ◽

Enzyme Prodrug Therapy ◽

Bacterial Gene ◽

Reducing Environment

We report herein a gene-directed enzyme prodrug therapy (GDEPT) system using gated mesoporous silica nanoparticles (MSNs) in an attempt to combine the reduction of side effects characteristic of GDEPT with improved pharmacokinetics promoted by gated MSNs. The system consists of the transfection of cancer cells with a plasmid controlled by the cytomegalovirus promoter, which promotes β-galactosidase (β-gal) expression from the bacterial gene lacZ (CMV-lacZ). Moreover, dendrimer-like mesoporous silica nanoparticles (DMSNs) are loaded with the prodrug doxorubicin modified with a galactose unit through a self-immolative group (DOXO-Gal) and modified with a disulfide-containing polyethyleneglycol gatekeeper. Once in tumor cells, the reducing environment induces disulfide bond rupture in the gatekeeper with the subsequent DOXO-Gal delivery, which is enzymatically converted by β-gal into the cytotoxic doxorubicin drug, causing cell death. The combined treatment of the pair enzyme/DMSNs-prodrug are more effective in killing cells than the free prodrug DOXO-Gal alone in cells transfected with β-gal.

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Calreticulin—Multifunctional Chaperone in Immunogenic Cell Death: Potential Significance as a Prognostic Biomarker in Ovarian Cancer Patients

Cells ◽

10.3390/cells10010130 ◽

2021 ◽

Vol 10 (1) ◽

pp. 130

Author(s):

Michal Kielbik ◽

Izabela Szulc-Kielbik ◽

Magdalena Klink

Keyword(s):

Ovarian Cancer ◽

Cell Death ◽

Cancer Patients ◽

Tumor Cells ◽

Cytotoxic T Cells ◽

Adaptive Immune Response ◽

Ovarian Cancer Cells ◽

Immunogenic Cell Death ◽

Antigen Presenting ◽

Molecular Patterns

Immunogenic cell death (ICD) is a type of death, which has the hallmarks of necroptosis and apoptosis, and is best characterized in malignant diseases. Chemotherapeutics, radiotherapy and photodynamic therapy induce intracellular stress response pathways in tumor cells, leading to a secretion of various factors belonging to a family of damage-associated molecular patterns molecules, capable of inducing the adaptive immune response. One of them is calreticulin (CRT), an endoplasmic reticulum-associated chaperone. Its presence on the surface of dying tumor cells serves as an “eat me” signal for antigen presenting cells (APC). Engulfment of tumor cells by APCs results in the presentation of tumor’s antigens to cytotoxic T-cells and production of cytokines/chemokines, which activate immune cells responsible for tumor cells killing. Thus, the development of ICD and the expression of CRT can help standard therapy to eradicate tumor cells. Here, we review the physiological functions of CRT and its involvement in the ICD appearance in malignant disease. Moreover, we also focus on the ability of various anti-cancer drugs to induce expression of surface CRT on ovarian cancer cells. The second aim of this work is to discuss and summarize the prognostic/predictive value of CRT in ovarian cancer patients.

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Biomarkers of Radiotherapy-Induced Immunogenic Cell Death

Cells ◽

10.3390/cells10040930 ◽

2021 ◽

Vol 10 (4) ◽

pp. 930

Author(s):

Rianne D. W. Vaes ◽

Lizza E. L. Hendriks ◽

Marc Vooijs ◽

Dirk De Ruysscher

Keyword(s):

Cell Death ◽

Immune Responses ◽

Tumor Cells ◽

Immunogenic Cell Death ◽

Type I ◽

Future Studies ◽

Regulated Cell Death ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns ◽

Potential Biomarkers

Radiation therapy (RT) can induce an immunogenic variant of regulated cell death that can initiate clinically relevant tumor-targeting immune responses. Immunogenic cell death (ICD) is accompanied by the exposure and release of damage-associated molecular patterns (DAMPs), chemokine release, and stimulation of type I interferon (IFN-I) responses. In recent years, intensive research has unraveled major mechanistic aspects of RT-induced ICD and has resulted in the identification of immunogenic factors that are released by irradiated tumor cells. However, so far, only a limited number of studies have searched for potential biomarkers that can be used to predict if irradiated tumor cells undergo ICD that can elicit an effective immunogenic anti-tumor response. In this article, we summarize the available literature on potential biomarkers of RT-induced ICD that have been evaluated in cancer patients. Additionally, we discuss the clinical relevance of these findings and important aspects that should be considered in future studies.

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