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Verteporfin-based photodynamic therapy overcomes gemcitabine insensitivity in a panel of pancreatic cancer cell lines.

ABSTRACT: Pancreatic cancer is notoriously difficult to treat and resistant to virtually all therapeutics including gemcitabine, the standard front line agent for palliative chemotherapy. Early clinical studies point to a potential role for photodynamic therapy (PDT) in the management of this deadly disease. Here we examine PDT with verteporfin for treatment of cells that are nonresponsive to gemcitabine and identify intracellular and extracellular factors that govern sensitivity to each modality.Using MTS we assess cytotoxicity of verteporfin-PDT in gemcitabine-treated nonresponsive populations from a panel of five pancreatic cancer cell lines representing a range of tumor histopathology and origin. We conduct Western blots for pro-/anti-apoptotic proteins bax and Bcl-XL to identify factors relevant to PDT and gemcitabine sensitivity. To examine the role of extracellular matrix influences we compare response to each modality in traditional cell culture conditions and cells grown on a laminin-rich basement membrane.All cell lines have gemcitabine nonresponsive populations (17-33%) at doses up to 1?mM while moderate total verteporfin PDT doses (1-6?µM?J/cm2) produce nearly complete killing. Our data shows that cells that are nonresponsive to sustained gemcitabine incubation are sensitive to verteporfin PDT indicating that the latter is agnostic to gemcitabine sensitivity. Verteporfin-based PDT decreases Bcl-XL and increases the bax/Bcl-XL ratio toward a pro-apoptotic balance. Insensitivity to gemcitabine is increased in cells that are adherent to basement membrane relative to traditional tissue culture conditions.Collectively these results indicate the ability of verteporfin-based PDT to bypass intracellular and extracellular cues leading to gemcitabine resistance and point to the emerging role of this therapy for treatment of pancreatic cancer.

SUBMITTER: Celli JP

PROVIDER: S-EPMC3211106 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Verteporfin-based photodynamic therapy overcomes gemcitabine insensitivity in a panel of pancreatic cancer cell lines.

Celli Jonathan P JP Solban Nicolas N Liang Alvin A Pereira Stephen P SP Hasan Tayyaba T

Lasers in surgery and medicine 20110901 7

<h4>Background and objective</h4>Pancreatic cancer is notoriously difficult to treat and resistant to virtually all therapeutics including gemcitabine, the standard front line agent for palliative chemotherapy. Early clinical studies point to a potential role for photodynamic therapy (PDT) in the management of this deadly disease. Here we examine PDT with verteporfin for treatment of cells that are nonresponsive to gemcitabine and identify intracellular and extracellular factors that govern sens ...[more]

PMID: 22057484

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Project description:With less than 10% of 5-year survival rate, pancreatic ductal adenocarcinoma (PDAC) is known to be one of the most lethal types of cancer. Current literature supports that gemcitabine is the first-line treatment of PDAC. However, poor cellular penetration of gemcitabine along with the acquired and intrinsic chemoresistance of tumor against it often reduced its efficacy and hence necessitates the administration of high gemcitabine dose during chemotherapy. Photodynamic therapy (PDT), a more selective and minimally invasive treatment, may be used synergistically with gemcitabine to reduce the doses utilized and dose-related side effects. This study reports the synergistic use of Re(I) bisquinolinyl complex, a transition metal complex photosensitizer with gemcitabine against PDAC. Re(I) bisquinolinyl complex was found to act synergistically with gemcitabine against PDAC in vitro at various ratios. With the aim to enhance cellular uptake and therapeutic efficiency, the Re(I) bisquinolinyl complex and gemcitabine were encapsulated into liquid crystalline nanoparticles (LCNPs) system. The formulations were found to produce homogeneous drug-loaded LCNPs (average size: 159-173 nm, zeta potential +1.06 to -10 mV). Around 70% of gemcitabine and 90% of the Re(I) bisquinolinyl complex were found to be entrapped efficiently in the formulated LCNPs. The release rate of gemcitabine or/and the Re(I) bisquinolinyl complex loaded into LCNPs was evaluated in vitro, and the hydrophilic gemcitabine was released at a faster rate than the lipophilic Re(I) complex. LCNPs loaded with gemcitabine and Re(I) bisquinolinyl complex in a 1:1 ratio illustrated the best anti-cancer activity among the LCNP formulations (IC50 of BxPC3: 0.15 μM; IC50 of SW 1990: 0.76 μM) through apoptosis. The current findings suggest the potential use of transition metal-based photosensitizer as an adjunctive agent for gemcitabine-based chemotherapy against PDAC and the importance of nano-formulation in such application.

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Verteporfin-based photodynamic therapy overcomes gemcitabine insensitivity in a panel of pancreatic cancer cell lines.

Publications

Verteporfin-based photodynamic therapy overcomes gemcitabine insensitivity in a panel of pancreatic cancer cell lines.

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