Failure of Pancreatic Cancer Chemotherapy: Consequences of Drug Resistance Mechanisms

Bhardwaj, Vikas; Tadinada, Satya Murthy; Lai, James C. K.; Bhushan, Alok

doi:10.5772/27122

Cited by 3 publications

(3 citation statements)

References 78 publications

(107 reference statements)

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“…The current treatment regimen for pancreatic cancer involves surgery, conventional radiotherapy and chemotherapy. However, the effectiveness of these treatments is limited by inherent or acquired drug resistance (3). Thus, new therapies are required to enhance the effectiveness of conventional treatments.…”

Section: Introductionmentioning

confidence: 99%

Radiosensitization of Pancreatic Cancer Cells by Metformin through the AMPK Pathway

et al. 2014

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Pancreatic cancer is relatively radioresistant, however, radiotherapy has been shown to provide efficacy in the treatment of local disease. To increase the effectiveness of radiotherapy in pancreatic cancer, radiosensitizing drugs are under development. In this study, we investigated the radiosensitizing activity of the anti-diabetic drug metformin on pancreatic cancer cells in vitro. We demonstrated that metformin radiosensitized MiaPaCa-2 and Panc1 cells with radiation enhancement ratios (ER) ranging from 1.33–1.45 with metformin concentrations of 30–100 μM, and in addition, we showed that metformin sensitized cells to gemcitabine alone or in combination with radiation treatment. In addition, we found that pancreatic cancer stem cell-like cells showed enhanced radiosensitization in a tumorsphere assay with a REF of 1.66. At these radiosensitizing doses, metformin alone had low toxicity (as shown by >75% clonogenic survival) and did not affect cell cycle. The combination of metformin and radiation yielded greater numbers of γ-H2AX foci after 1 h compared to radiation alone, suggesting increased DNA damage signaling. Examination of the AMPK pathway showed that pharmacological inhibition of AMPK signaling or RNAi of AMPKα1 reversed metformin-mediated radiosensitization. These studies show that metformin radiosensitization of pancreatic cancer cells at micromolar concentration acts through AMPK and may affect DNA damage signaling. The data indicate that metformin may increase the efficacy of radiation therapy for pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

Radiosensitization of Pancreatic Cancer Cells by Metformin through the AMPK Pathway

et al. 2014

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“…Currently, only gemcitabine and fluorouracil have been used consistently to improve the survival of pancreatic patients with marginal survival advantage. 27 More recently, several attempts have been made to find new agents derived from plants which are safe, available and effective against pancreatic cancer. Curcumin has been shown to enhance the antitumor activity of gemcitabine and to suppress NFjB activation with potent capability to control invasion, migration and induce apoptosis.…”

Section: Discussionmentioning

confidence: 99%

In vitro antimetastatic activity of Agarwood (Aquilaria crassna) essential oils against pancreatic cancer cells

Dahham

Tabana

Hassan

et al. 2016

Alexandria Journal of Medicine

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Background: Pancreatic cancer is one of the most lethal malignant tumors which remains a rampant killer across the globe. Lack of early diagnosis and toxic drugs have failed to improve the survival rate of pancreatic cancer patients, thus new agents that are safe, available and effective are urgently needed. Objective: The study aimed to investigate the efficacy of Agarwood essential oils in the inhibition of metastasis and induction of apoptosis in the pancreatic cell line (MIA PaCa-2). Methods: Essential oils of Aquilaria crassna were obtained by hydrodistillation. Chemical characterization was analyzed using FTIR and GCMS. The effects of essential oils against three steps of metastases have been investigated, including cell proliferation, migration and clonogenicity. Hoechst and rhodamine assays confirmed the mechanism of pancreatic cancer cell death. Results: The results showed that essential oils exhibited potent cytotoxic activity against MIA PaCa-2 cells with an IC 50 (11 ± 2.18 lg/ml). Cell migration was effectively inhibited at (10 lg/ml). Moreover, at a sub-toxic dose (5 lg/mL), essential oils obstructed the colony formation properties of MIA PaCa-2 significantly. The mechanism of cell death was determined due to the

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“…Many reviews [9][10][11][22][23][24][25] have thoroughly examined the mechanisms of action of, and resistance to, gemcitabine in pancreatic cancer cells, detailing the steps of intra-and extracellular drug transportation [26][27][28][29] , metabolic activation of gemcitabine [30][31][32][33][34][35] , molecular pathways that combat drug-induced apoptosis [36][37][38][39][40][41] , pro-oncogenic pathways that enable tumor cells to survive cytotoxic effects [36,[42][43][44][45][46][47][48][49][50][51] , and epithelial-mesenchymal transition (EMT), a pro-invasive tumor property [52,53] . These reviews [10,11,[22][23][24][25] also discuss the role of specific micro-RNAs in altering the expression of molecules linked to gemcitabine resistance.…”

Section: Mechanisms Of Gemcitabine Resistance In Pancreatic Cancermentioning

confidence: 99%

Glycogen synthase kinase 3β: the nexus of chemoresistance, invasive capacity, and cancer stemness in pancreatic cancer

Uehara,

Domoto,

Takenaka

et al. 2024

Cancer Drug Resist

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The treatment of pancreatic cancer remains a significant clinical challenge due to the limited number of patients eligible for curative (R0) surgery, failures in the clinical development of targeted and immune therapies, and the pervasive acquisition of chemotherapeutic resistance. Refractory pancreatic cancer is typified by high invasiveness and resistance to therapy, with both attributes related to tumor cell stemness. These malignant characteristics mutually enhance each other, leading to rapid cancer progression. Over the past two decades, numerous studies have produced evidence of the pivotal role of glycogen synthase kinase (GSK)3β in the progression of over 25 different cancer types, including pancreatic cancer. In this review, we synthesize the current knowledge on the pathological roles of aberrant GSK3β in supporting tumor cell proliferation and invasion, as well as its contribution to gemcitabine resistance in pancreatic cancer. Importantly, we discuss the central role of GSK3β as a molecular hub that mechanistically connects chemoresistance, tumor cell invasion, and stemness in pancreatic cancer. We also discuss the involvement of GSK3β in the formation of desmoplastic tumor stroma and in promoting anti-cancer immune evasion, both of which constitute major obstacles to successful cancer treatment. Overall, GSK3β has characteristics of a promising therapeutic target to overcome chemoresistance in pancreatic cancer.

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Failure of Pancreatic Cancer Chemotherapy: Consequences of Drug Resistance Mechanisms

Cited by 3 publications

References 78 publications

Radiosensitization of Pancreatic Cancer Cells by Metformin through the AMPK Pathway

Radiosensitization of Pancreatic Cancer Cells by Metformin through the AMPK Pathway

In vitro antimetastatic activity of Agarwood (Aquilaria crassna) essential oils against pancreatic cancer cells

Glycogen synthase kinase 3β: the nexus of chemoresistance, invasive capacity, and cancer stemness in pancreatic cancer

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