Unraveling the complexity of autophagy: Potential therapeutic applications in Pancreatic Ductal Adenocarcinoma

Gomez, Valentina; Giovannetti, Elisa; Peters, Godefridus J.

doi:10.1016/j.semcancer.2015.09.011

Cited by 35 publications

(21 citation statements)

References 46 publications

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“…8 Some studies have demonstrated that verteporfin could be delivered to cancer cells with a much shorter time interval between drug administration and photoactivation and with less photosensitivity than the older generation photosensitizers. 8,41,42 Our study confirmed that sodium porfimer and verteporfin-PDT induced death in pancreatic cancer in a dose-dependent manner as reported by other groups. 3,9,35 In this study, we observed that all cell lines had nonresponsive populations at lower and moderate doses of both the photosensitizers.…”

Section: Discussionsupporting

confidence: 90%

Verteporfin- and sodium porfimer-mediated photodynamic therapy enhances pancreatic cancer cell death without activating stromal cells in the microenvironment

Roy

Anderson

et al. 2019

J. Biomed. Opt.

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The goal of our study was to determine the susceptibility of different pancreatic cell lines to clinically applicable photodynamic therapy (PDT). The efficacy of PDT of two different commercially available photosensitizers, verteporfin and sodium porfimer, was compared using a panel of four different pancreatic cancer cell lines, PANC-1, BxPC-3, CAPAN-2, and MIA PaCa-2, and an immortalized non-neoplastic pancreatic ductal epithelium cell line, HPNE. The minimum effective concentrations and dose-dependent curves of verteporfin and sodium porfimer on PANC-1 were determined. Since pancreatic cancer is known to have significant stromal components, the effect of PDT on stromal cells was also assessed. To mimic tumor-stroma interaction, a coculture of primary human fibroblasts or human pancreatic stellate cell (HPSCs) line with PANC-1 was used to test verteporfin-PDT-mediated cell death of PANC-1. Two cytokines (TNF-α and IL-1β) were used for stimulation of primary fibroblasts (derived from human esophageal biopsies) or HPSCs. The increased expression of smooth muscle actin (α-SMA) confirmed the activation of fibroblasts or HPSC upon treatment with TNF-α and IL-1β. Cell death assays showed that both sodium porfimer-and verteporfin-mediated PDT-induced cell death in a dose-dependent manner. However, verteporfin-PDT treatment had a greater efficiency with 60× lower concentration than sodium porfimer-PDT in the PANC-1 incubated with stimulated fibroblasts or HPSC. Moreover, activation of stromal cells did not affect the treatment of the pancreatic cancer cell lines, suggesting that the effects of PDT are independent of the inflammatory microenvironment found in this two-dimensional culture model of cancers.

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Section: Discussionsupporting

confidence: 90%

Verteporfin- and sodium porfimer-mediated photodynamic therapy enhances pancreatic cancer cell death without activating stromal cells in the microenvironment

Roy

Anderson

et al. 2019

J. Biomed. Opt.

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“…A phase II study of the related agent hydroxychloroquine as a monotherapy 113 , however, failed to show consistent inhibition of autophagy or therapeutic efficacy. Combination with cytotoxic drugs has been proposed as a strategy to overcome the need for complete inhibition of the autophagic response; therefore, chloroquine and the related agent hydroxychloroquine are now being used to target autophagy in combination with cytotoxic agents (such as gemcitabine and nab-paclitaxel) in a number of early phase clinical trials in patients with PDAC 66,[114][115][116] and NCT01777477 (REF. 121)).…”

Section: Improving the Efficacy Of Gemcitabinementioning

confidence: 99%

Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer

et al. 2016

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Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer- related deaths. PDAC remains one of the most difficult-to-treat cancers, owing to its unique pathobiological features: a nearly impenetrable desmoplastic stroma, and hypovascular and hypoperfused tumour vessels render most treatment options largely ineffective. Progress in understanding the pathobiology and signalling pathways involved in disease progression is helping researchers to develop novel ways to fight PDAC, including improved nanotechnology-based drug-delivery platforms that have the potential to overcome the biological barriers of the disease that underlie persistent drug resistance. So-called 'nanomedicine' strategies have the potential to enable targeting of the Hedgehog-signalling pathway, the autophagy pathway, and specific RAS-mutant phenotypes, among other pathological processes of the disease. These novel therapies, alone or in combination with agents designed to disrupt the pathobiological barriers of the disease, could result in superior treatments, with increased efficacy and reduced off-target toxicities compared with the current standard-of-care regimens. By overcoming drug-delivery challenges, advances can be made in the treatment of PDAC, a disease for which limited improvement in overall survival has been achieved over the past several decades. We discuss the approaches to nanomedicine that have been pursued to date and those that are the focus of ongoing research, and outline their potential, as well as the key challenges that must be overcome.

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“…These results might be relevant for PDAC because some research lines point at autophagy as a tumor-promoting mechanism. Although a better understanding of the complexity of autophagy is needed, the modulation of this process might therefore open new opportunities for the therapeutic use of autophagy inhibitors [54]. Further research to identify the precise mechanisms of autophagy maturation may therefore provide a new insight into the antiproliferative action of perifosine.…”

Section: Discussionmentioning

confidence: 99%

Phospho-Akt overexpression is prognostic and can be used to tailor the synergistic interaction of Akt inhibitors with gemcitabine in pancreatic cancer

et al. 2017

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BackgroundThere is increasing evidence of a constitutive activation of Akt in pancreatic ductal adenocarcinoma (PDAC), associated with poor prognosis and chemoresistance. Therefore, we evaluated the expression of phospho-Akt in PDAC tissues and cells, and investigated molecular mechanisms influencing the therapeutic potential of Akt inhibition in combination with gemcitabine.MethodsPhospho-Akt expression was evaluated by immunohistochemistry in tissue microarrays (TMAs) with specimens tissue from radically-resected patients (n = 100). Data were analyzed by Fisher and log-rank test. In vitro studies were performed in 14 PDAC cells, including seven primary cultures, characterized for their Akt1 mRNA and phospho-Akt/Akt levels by quantitative-RT-PCR and immunocytochemistry. Growth inhibitory effects of Akt inhibitors and gemcitabine were evaluated by SRB assay, whereas modulation of Akt and phospho-Akt was investigated by Western blotting and ELISA. Cell cycle perturbation, apoptosis-induction, and anti-migratory behaviors were studied by flow cytometry, AnnexinV, membrane potential, and migration assay, while pharmacological interaction with gemcitabine was determined with combination index (CI) method.ResultsImmunohistochemistry of TMAs revealed a correlation between phospho-Akt expression and worse outcome, particularly in patients with the highest phospho-Akt levels, who had significantly shorter overall and progression-free-survival. Similar expression levels were detected in LPC028 primary cells, while LPC006 were characterized by low phospho-Akt. Remarkably, Akt inhibitors reduced cancer cell growth in monolayers and spheroids and synergistically enhanced the antiproliferative activity of gemcitabine in LPC028, while this combination was antagonistic in LPC006 cells. The synergistic effect was paralleled by a reduced expression of ribonucleotide reductase, potentially facilitating gemcitabine cytotoxicity. Inhibition of Akt decreased cell migration and invasion, which was additionally reduced by the combination with gemcitabine. This combination significantly increased apoptosis, associated with induction of caspase-3/6/8/9, PARP and BAD, and inhibition of Bcl-2 and NF-kB in LPC028, but not in LPC006 cells. However, targeting the key glucose transporter Glut1 resulted in similar apoptosis induction in LPC006 cells.ConclusionsThese data support the analysis of phospho-Akt expression as both a prognostic and a predictive biomarker, for the rational development of new combination therapies targeting the Akt pathway in PDAC. Finally, inhibition of Glut1 might overcome resistance to these therapies and warrants further studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0371-1) contains supplementary material, which is available to authorized users.

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Unraveling the complexity of autophagy: Potential therapeutic applications in Pancreatic Ductal Adenocarcinoma

Cited by 35 publications

References 46 publications

Verteporfin- and sodium porfimer-mediated photodynamic therapy enhances pancreatic cancer cell death without activating stromal cells in the microenvironment

Verteporfin- and sodium porfimer-mediated photodynamic therapy enhances pancreatic cancer cell death without activating stromal cells in the microenvironment

Nanomedicine strategies to overcome the pathophysiological barriers of pancreatic cancer

Phospho-Akt overexpression is prognostic and can be used to tailor the synergistic interaction of Akt inhibitors with gemcitabine in pancreatic cancer

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