Enhanced Antitumor Effect of Combined Gemcitabine and Proton Radiation in the Treatment of Pancreatic Cancer

Galloway, Nicholas R.; Aspe, Jonathan R.; Sellers, Chelsey; Wall, Nathan R.

doi:10.1097/mpa.0b013e3181a85999

Cited by 15 publications

(26 citation statements)

References 36 publications

(41 reference statements)

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“…Conversely, inhibition of Survivin reduces tumor growth potential and sensitizes tumor cells to chemotherapeutic agents, such as paclitaxel, cisplatin, etoposide, gamma irradiation, and immunotherapy [48]. More recently, we have investigated Survivin’s role in resistance to proton irradiation of pancreatic cancer cells and found that stress proteins such as Survivin and the X-linked inhibitor of apoptosis (XIAP) protein play important roles in resistance to proton-based treatment options [49]. We therefore investigated whether stress, delivered by proton irradiation to HeLaS/POZnSurvivin cells, stimulated enhanced Survivin release to the extracellular conditioned medium compared with control conditions.…”

Section: Resultsmentioning

confidence: 99%

Survivin is released from cancer cells via exosomes

et al. 2010

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Inhibitor of apoptosis (IAP) and Heat shock proteins (HSPs) provide assistance in protecting cells from stresses of hypoxia, imbalanced pH, and altered metabolic and redox states commonly found in the microenvironmental mixture of tumor and nontumor cells. HSPs are upregulated, cell-surface displayed and released extracellularly in some types of tumors, a finding that until now was not shared by members of the IAP family. The IAP Survivin has been implicated in apoptosis inhibition and the regulation of mitosis in cancer cells. Survivin exists in a number of subcellular locations such as the mitochondria, cytoplasm, nucleus, and most recently, the extracellular space. Our previous work showing that extracellular survivin was able to enhance cellular proliferation, survival and tumor cell invasion provides evidence that Survivin might be secreted via an unidentified exocytotic pathway. In the present study, we describe for the first time the exosome-release of Survivin to the extracellular space both basally and after proton irradiation-induced stress. To examine whether exosomes contributed to Survivin release from cancer cells, exosomes were purified from HeLa cervical carcinoma cells and exosome quantity and Survivin content were determined. We demonstrate that although proton irradiation does not influence the exosomal secretory rate, the Survivin content of exosomes isolated from HeLa cells treated with a sublethal dose of proton irradiation (3 Gy) is significantly higher than control. These data identify a novel secretory pathway by which Survivin can be actively released from cells in both the basal and stress-induced state.

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Section: Resultsmentioning

confidence: 99%

Survivin is released from cancer cells via exosomes

et al. 2010

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“…Furthermore, NF-kB activity and IAP expression have been implicated in resistance to Gemcitabine (69-70). Gemcitabine induces an increase in IAP expression in pancreatic cancer cells, particularly Survivin and XIAP, as well as cIAP1 in lung cancer cells (71-74). …”

Section: Discussionmentioning

confidence: 99%

Curcumin Induces Pancreatic Adenocarcinoma Cell Death Via Reduction of the Inhibitors of Apoptosis

Osterman¹,

Gonda²,

Stiff³

et al. 2016

Pancreas

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Objectives The inhibitor of apoptosis (IAP) proteins are critical modulators of chemotherapeutic resistance in various cancers. To address the alarming emergence of chemotherapeutic resistance in pancreatic cancer, we investigated the efficacy of the turmeric derivative curcumin in reducing IAP protein and mRNA expression resulting in pancreatic cancer cell death. Methods The pancreatic adenocarcinoma cell line PANC-1 was used to assess curcumin’s effects in pancreatic cancer. Curcumin uptake was measured by spectral analysis and fluorescence microscopy. AlamarBlue and Trypan blue exclusion assays were used to determine PANC-1 cell viability following curcumin treatment. Visualization of PANC-1 cell death was performed using Hoffman Modulation Contrast microscopy. Western blot and PCR analyses were used to evaluate curcumin’s effects on IAP protein and mRNA expression. Results Curcumin enters PANC-1 cells and is ubiquitously present within the cell following treatment. Furthermore, curcumin reduces cell viability and induces morphological changes characteristic of cell death. Additionally, curcumin decreases IAP protein and mRNA expression in PANC-1 cells. Conclusions These data demonstrate that PANC-1 cells are sensitive to curcumin treatment. Furthermore, curcumin as a potential therapeutic tool for overcoming chemotherapeutic resistance mediated by IAPs, supports a role for curcumin as part of the therapeutic approach for pancreatic cancer.

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“…This can be due to a decrease in levels of endogenous IAP inhibitors, abnormalities in the gene, or an increase in the expression of either mRNA or protein 40. Specifically, the high levels of survivin expression in cancer cells have been associated with dismal prognosis, disease progression, metastatic dissemination, chemo- and radiotherapy resistance, and overall dismal disease outcome 28,41,42. In many cancer types, such as glioblastoma, renal cell carcinoma, and liver and pancreatic cancer, the chromosome region of 11q21–23, which includes both the cIAP1 and cIAP2 genes, is shown to be amplified in these diseases, making cIAP1/2 protooncogenes.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous efforts have been made to target these IAPs to address the problem with resistance to therapy. XIAP silencing by siRNA in pancreatic cancer cell lines has been shown to increase Gem sensitivity,45 as well as an enhancement of cell death when treated with both Gem and proton radiation 42. Other studies have targeted survivin, showing that knocking this IAP down with siRNA caused Gem chemosensitivity 46.…”

Section: Discussionmentioning

confidence: 99%

Cell death in response to antimetabolites directed at ribonucleotide reductase and thymidylate synthase

Valenzuela¹,

Castro²,

Gonda³

et al. 2015

OTT

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New agent development, mechanistic understanding, and combinatorial partnerships with known and novel modalities continue to be important in the study of pancreatic cancer and its improved treatment. In this study, known antimetabolite drugs such as gemcitabine (ribonucleotide reductase inhibitor) and 5-fluorouracil (thymidylate synthase inhibitor) were compared with novel members of these two drug families in the treatment of a chemoresistant pancreatic cancer cell line PANC-1. Cellular survival data, along with protein and messenger ribonucleic acid expression for survivin, XIAP, cIAP1, and cIAP2, were compared from both the cell cytoplasm and from exosomes after single modality treatment. While all antimetabolite drugs killed PANC-1 cells in a time- and dose-dependent manner, neither family significantly altered the cytosolic protein level of the four inhibitors of apoptosis (IAPs) investigated. Survivin, XIAP, cIAP1, and cIAP2 were found localized to exosomes where no significant difference in expression was recorded. This inability for significant and long-lasting expression may be a reason why pancreatic cancer lacks responsiveness to these and other cancer-killing agents. Continued investigation is required to determine the responsibilities of these IAPs in their role in chemoresistance in pancreatic adenocarcinoma.

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Enhanced Antitumor Effect of Combined Gemcitabine and Proton Radiation in the Treatment of Pancreatic Cancer

Cited by 15 publications

References 36 publications

Survivin is released from cancer cells via exosomes

Survivin is released from cancer cells via exosomes

Curcumin Induces Pancreatic Adenocarcinoma Cell Death Via Reduction of the Inhibitors of Apoptosis

Cell death in response to antimetabolites directed at ribonucleotide reductase and thymidylate synthase

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