Target Nanoparticles against Pancreatic Cancer: Fewer Side Effects in Therapy

Pancreatic cancer is the most common lethal tumor in America. This lethality is related to limited treatment options. Conventional treatments involve the non-specific use of chemotherapeutical agents such as 5-FU, capecitabine, gemcitabine, paclitaxel, cisplatin, oxaliplatin, or irinotecan, which produce several side effects. This review focuses on the use of targeted nanoparticles, such as metallic nanoparticles, polymeric nanoparticles, liposomes, micelles, and carbon nanotubes as an alternative to standard treatment for pancreatic cancer. The principal objective of nanoparticles is reduction of the side effects that conventional treatments produce, mostly because of their non-specificity. Several molecular markers of pancreatic cancer cells have been studied to target nanoparticles and improve current treatment. Therefore, properly functionalized nanoparticles with specific aptamers or antibodies can be used to recognize pancreatic cancer cells. Once cancer is recognized, these nanoparticles can attack the tumor by drug delivery, gene therapy, or hyperthermia.

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Target Nanoparticles Against Pancreatic Cancer: Fewer Side Effects in Therapy

10.20944/preprints202110.0187.v1 ◽

2021 ◽

Author(s):

Jorge A Roacho-Pérez ◽

Elsa N Garza-Treviño ◽

Paulina Delgado-Gonzalez ◽

Zuca G-Buentello ◽

Juan Luis Delgado-Gallegos ◽

...

Keyword(s):

Pancreatic Cancer ◽

Gene Therapy ◽

Side Effects ◽

Cancer Cells ◽

Standard Treatment ◽

Treatment Options ◽

Actual Treatment ◽

Targeted Nanoparticles ◽

Pancreatic Cancer Cells ◽

Or Gene

Pancreatic cancer leads the most common lethal tumor in America. This lethality is related to limited treatment options. Conventional treatments involve a non-specific use of chemotherapeutical agents like 5-FU, capecitabine, gemcitabine, cisplatine, oxaliplatine, or irinotecan, that produce several side effects. This review we focus on the use of targeted nanoparticles as an alternative to the standard treatment for the pancreatic cancer. The principal objective of the use of nanoparticles is the reduction in side effects that conventional treatments produce, mostly because of their nonspecificity. Currently, several molecular markets of pancreatic cancer cells have been studied to target nanoparticles and improve the actual treatment. Therefore, properly functionalizated nanoparticles with specific aptamers or antibodies can be used to recognize pancreatic cancer cells and once cancer is recognized, these nanoparticles can attack the tumor by drug delivery, hyperthermia, or gene therapy.

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Cerium Oxide Nanoparticles Sensitize Pancreatic Cancer to Radiation Therapy through Oxidative Activation of the JNK Apoptotic Pathway

Cancers ◽

10.3390/cancers10090303 ◽

2018 ◽

Vol 10 (9) ◽

pp. 303 ◽

Cited By ~ 9

Author(s):

Melissa Wason ◽

Heng Lu ◽

Lin Yu ◽

Satadru Lahiri ◽

Debarati Mukherjee ◽

...

Keyword(s):

Pancreatic Cancer ◽

Radiation Therapy ◽

Side Effects ◽

Cancer Cells ◽

Cerium Oxide ◽

Mitotic Catastrophe ◽

Cerium Oxide Nanoparticles ◽

Oxide Nanoparticles ◽

Pancreatic Cancer Cells ◽

Jnk Activation

Side effects of radiation therapy (RT) remain the most challenging issue for pancreatic cancer treatment. Cerium oxide nanoparticles (CONPs) are currently being tested in pre-clinical trials as an adjuvant to sensitize pancreatic cancer cells to RT and protect normal tissues from the harmful side effects. CONPs were not able to significantly affect RT-induced DNA damage in cancer cells, thereby ruling out sensitization through increased mitotic catastrophe. However, activation of c-Jun terminal kinase (JNK), a key driver of RT-induced apoptosis, was significantly enhanced by co-treatment with CONPs and RT in pancreatic cancer cells in vitro and human pancreatic tumors in nude mice in vivo compared to CONPs or RT treatment alone. Further, CONP-driven increase in RT-induced JNK activity was associated with a marked increase in Caspase 3/7 activation, indicative of apoptosis. We have previously shown that CONPs increase reactive oxygen species (ROS) production in cancer cells. ROS has been shown to drive the oxidation of thioredoxin 1 (TRX1) which results in the activation of apoptosis signaling kinase 1 (ASK1). The increase in ASK1 activation following the co-treatment with CONPs followed by RT suggests that the increased JNK activation is the result of increased TRX1 oxidation. The ability of CONPs to sensitize pancreatic cancer cells to RT was mitigated when the TRX1 oxidation was prevented by mutagenesis of a cysteine residue or when the JNK activation was blocked by an inhibitor. Taken together, these data demonstrate an important mechanism for CONPs in specifically killing cancer cells and provide novel insights into the utilization of CONPs as a radiosensitizer and therapeutic agent for pancreatic cancer.

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Metabolic plasticity imparts erlotinib-resistance in pancreatic cancer by upregulating glucose-6-phosphate dehydrogenase

Cancer & Metabolism ◽

10.1186/s40170-020-00226-5 ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Neha Sharma ◽

Alok Bhushan ◽

Jun He ◽

Gagan Kaushal ◽

Vikas Bhardwaj

Keyword(s):

Pancreatic Cancer ◽

Drug Resistance ◽

Cancer Cells ◽

Treatment Options ◽

Pentose Phosphate ◽

Metabolic Phenotype ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells ◽

Glucose 6 Phosphate Dehydrogenase ◽

Resistant Cells

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant forms of cancer. Lack of effective treatment options and drug resistance contributes to the low survival among PDAC patients. In this study, we investigated the metabolic alterations in pancreatic cancer cells that do not respond to the EGFR inhibitor erlotinib. We selected erlotinib-resistant pancreatic cancer cells from MiaPaCa2 and AsPC1 cell lines. Metabolic profiling of erlotinib-resistant cells revealed a significant downregulation of glycolytic activity and reduced level of glycolytic metabolites compared to the sensitive cells. The resistant cells displayed elevated expression of the pentose phosphate pathway (PPP) enzymes involved in ROS regulation and nucleotide biosynthesis. The enhanced PPP elevated cellular NADPH/NADP+ ratio and protected the cells from reactive oxygen species (ROS)-induced damage. Inhibition of PPP using 6-aminonicotinamide (6AN) elevated ROS levels, induced G1 cell cycle arrest, and sensitized resistant cells to erlotinib. Genetic studies identified elevated PPP enzyme glucose-6-phosphate dehydrogenase (G6PD) as an important contributor to erlotinib resistance. Mechanistically, our data showed that upregulation of inhibitor of differentiation (ID1) regulates G6PD expression in resistant cells thus contributing to altered metabolic phenotype and reduced response to erlotinib. Together, our results highlight an underlying role of tumor metabolism in PDAC drug response and identify G6PD as a target to overcome drug resistance.

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Colloidal Nanocarriers as Versatile Targeted Delivery Systems for Cervical Cancer

Current Pharmaceutical Design ◽

10.2174/1381612826666200625110950 ◽

2020 ◽

Vol 26 (40) ◽

pp. 5174-5187 ◽

Cited By ~ 1

Author(s):

Abimanyu Sugumaran ◽

Vishali Mathialagan

Keyword(s):

Cervical Cancer ◽

Side Effects ◽

Anticancer Agents ◽

Targeted Delivery ◽

Metallic Nanoparticles ◽

Polymeric Nanoparticles ◽

Survival Rates ◽

Cost Effective ◽

Current Treatment ◽

Normal Tissues

Background: The second most common malignant cancer of the uterus is cervical cancer, which is present worldwide, has a rising death rate and is predominant in developing countries. Different classes of anticancer agents are used to treat cervical carcinoma. The use of these agents results in severe untoward side-effects, toxicity, and multidrug resistance (MDR) with higher chances of recurrence and spread beyond the pelvic region. Moreover, the resulting clinical outcome remains very poor even after surgical procedures and treatment with conventional chemotherapy. Because of the nonspecificity of their use, the agents wipe out both cancerous and normal tissues. Colloidal nano dispersions have now been focusing on site-specific delivery for cervical cancer, and there has been much advancement. Methods: This review aims to highlight the problems in the current treatment of cervical cancer and explore the potential of colloidal nanocarriers for selective delivery of anticancer drugs using available literature. Results: In this study, we surveyed the role and potential of different colloidal nanocarriers in cervical cancer, such as nanoemulsion, nanodispersions, polymeric nanoparticles, and metallic nanoparticles and photothermal and photodynamic therapy. We found significant advancement in colloidal nanocarrier-based cervical cancer treatment. Conclusion: Cervical cancer-targeted treatment with colloidal nanocarriers would hopefully result in minimal toxic side effects, reduced dosage frequency, and lower MDR incidence and enhance the patient survival rates. The future direction of the study should be focused more on the regulatory barrier of nanocarriers based on clinical outcomes for cervical cancer targeting with cost-effective analysis.

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Cysteine catabolism and the serine biosynthesis pathway support pyruvate production during pyruvate kinase knockdown in pancreatic cancer cells

Cancer & Metabolism ◽

10.1186/s40170-019-0205-z ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 8

Author(s):

Lei Yu ◽

Shao Thing Teoh ◽

Elliot Ensink ◽

Martin P. Ogrodzinski ◽

Che Yang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Pyruvate Kinase ◽

Metabolic Pathways ◽

Treatment Options ◽

Ductal Adenocarcinoma ◽

Metabolic Enzyme ◽

Biosynthesis Pathway ◽

Pancreatic Cancer Cells ◽

Serine Biosynthesis

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options. Pyruvate kinase, especially the M2 isoform (PKM2), is highly expressed in PDAC cells, but its role in pancreatic cancer remains controversial. To investigate the role of pyruvate kinase in pancreatic cancer, we knocked down PKM2 individually as well as both PKM1 and PKM2 concurrently (PKM1/2) in cell lines derived from a KrasG12D/-; p53-/- pancreatic mouse model. Methods We used liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine metabolic profiles of wildtype and PKM1/2 knockdown PDAC cells. We further used stable isotope-labeled metabolic precursors and LC-MS/MS to determine metabolic pathways upregulated in PKM1/2 knockdown cells. We then targeted metabolic pathways upregulated in PKM1/2 knockdown cells using CRISPR/Cas9 gene editing technology. Results PDAC cells are able to proliferate and continue to produce pyruvate despite PKM1/2 knockdown. The serine biosynthesis pathway partially contributed to pyruvate production during PKM1/2 knockdown: knockout of phosphoglycerate dehydrogenase in this pathway decreased pyruvate production from glucose. In addition, cysteine catabolism generated ~ 20% of intracellular pyruvate in PDAC cells. Other potential sources of pyruvate include the sialic acid pathway and catabolism of glutamine, serine, tryptophan, and threonine. However, these sources did not provide significant levels of pyruvate in PKM1/2 knockdown cells. Conclusion PKM1/2 knockdown does not impact the proliferation of pancreatic cancer cells. The serine biosynthesis pathway supports conversion of glucose to pyruvate during pyruvate kinase knockdown. However, direct conversion of serine to pyruvate was not observed during PKM1/2 knockdown. Investigating several alternative sources of pyruvate identified cysteine catabolism for pyruvate production during PKM1/2 knockdown. Surprisingly, we find that a large percentage of intracellular pyruvate comes from cysteine. Our results highlight the ability of PDAC cells to adaptively rewire their metabolic pathways during knockdown of a key metabolic enzyme.

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