Sensitising pancreatic cancer cell lines to electrochemotherapy by modulation of the cell cycle

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Cooke, Katie Deniese
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University College Cork
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We chose to research pancreatic cancer as pancreatic adenocarcinoma (PAC) is quite the aggressive disease, which even with the vast improvements in cancer treatments over recent years still has limited treatment options. Monotherapy treatment of pancreatic cancer with chemotherapy drugs initially show hopeful results, decreased disease symptoms and can lead to a slight improvement in survival but unfortunately does often ends in recurrence (1–3). Surgery has shown to be successful for respectable tumours followed by chemotherapy. Chemotherapy alone has proven to be associated with chemoresistance and can be quite intense, often patients are not able to continue with strong treatment regimes. FOLFIRINOX is classed as the gold standard for treating PAC, however, patient fitness ultimately determines suitability. Electrochemotherapy (ECT) is a new and emerging cancer therapy which allows for decreased doses of chemotherapy drugs to be used. We have evaluated pancreatic cancer cell lines response to low dose chemotherapy and Electrochemotherapy. The human pancreatic cell lines BxPC-3, PANC-1, and MIAPaCa-2 were used for all experiments in this thesis. Based on previous studies we predicted that PANC-1 cells would be most resistant to drug treatment followed by BxPC-3 and MIAPaCa-2 cells. All cell lines survived treatment with Gemcitabine (GEM) and Nab-paclitaxel (Nab), however, they had decreased survival when treated with 5’Fluorouracil (5’FU). When Electrochemotherapy (ECT) was applied to the cell line using GEM, Nab and 5’FU, cells survived and recovered but again had decreased survival and recovery with 5’FU ECT. Cells were also treated with Oxaliplatin (Ox) ECT, this had more of an impact to cell survival than with GEM/Nab/5’FU ECT. Bleomycin and cisplatin are the conventional drugs used with ECT due to their effectiveness (4,5), but we chose Ox as it is part of the FOLFIRONOX cocktail which is the gold standard for treating patients with PAC. Electrochemotherapy (ECT) has emerged as a promising treatment strategy for patients with pancreatic cancer (PC). ECT is safe for patients and has reduced side effects of systemic chemotherapy as drugs are concentrated to treatment site(6). ECT has shown to be very effective in treating melanoma (7). ECT has recently been used to treat locally advanced PC (8). Development of preclinical and clinical agents that inhibit cell cycle progression have proven effective in the treatment of cancer. Targeting cyclin dependent kinases (CDKs) and cell cycle checkpoint proteins can induce cell cycle arrest and apoptosis in cancer cells. Cell cycle deregulation is regularly seen in pancreatic cancer. Cells grow out of control and can lead to mortality. Controlling the deregulation with cell cycle inhibitors has shown to be beneficial for survival. Our study aimed to investigate CDK4/6 inhibitors and their ability to inhibit cell cycle progression. We specifically chose CDK4/6 inhibitors as they have proven to be quite effective in previous studies of breast cancer(9). Our hypothesis was that using a cell cycle inhibitor as a pre-treatment to ECT would make cells more susceptible to treatment. We used Palbociclib (PAL), a CDK4 inhibitor which causes cell cycle arrest at G1 and prevents cells progressing to S phase. We carried out experiments to investigate CDK4 levels in cells treated with PAL and cell cycle profiles of these cells post treatment. PAL prevents cell from passing to S phase of the cell cycle. We could not finish our planned work due to time, ceased funding and the COVID-19 global pandemic. We theorise that this combination treatment could enhance the efficiency of ECT and could potentially be translated into a clinical study as a new treatment option and improve patient quality of life.
Electrochemotherapy , Pancreatic cancer
Cooke, K. D. 2021. Sensitising pancreatic cancer cell lines to electrochemotherapy by modulation of the cell cycle. MRes Thesis, University College Cork.