Targeting and Treatment of Tumor Hypoxia by Newly Designed Prodrug Possessing High Permeability in Solid Tumors

Ikeda, Yutaka; Hisano, Hikaru; Nishikawa, Yuji; Nagasaki, Yukio

doi:10.1021/acs.molpharmaceut.6b00011

Cited by 40 publications

(30 citation statements)

References 20 publications

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“…Before treatment, administration of antiangiogenic therapy can help to remove extra capillaries and abnormal blood vessels leading to a reduction in the pressure of the interstitial fluid [ 239 , 240 , 241 , 242 ]. Other suggestions include damaging already existing blood vessels leading to solid tumor vessel permeability and increased drug delivery [ 184 , 243 , 244 , 245 ]. It should be recalled however that several strategies that target tumors inadvertently affect normal tissues as well.…”

Section: Strategies To Overcome Chemoresistancementioning

confidence: 99%

The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer

Senthebane

Rowe

Thomford

et al. 2017

IJMS

334

330

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Chemoresistance is a leading cause of morbidity and mortality in cancer and it continues to be a challenge in cancer treatment. Chemoresistance is influenced by genetic and epigenetic alterations which affect drug uptake, metabolism and export of drugs at the cellular levels. While most research has focused on tumor cell autonomous mechanisms of chemoresistance, the tumor microenvironment has emerged as a key player in the development of chemoresistance and in malignant progression, thereby influencing the development of novel therapies in clinical oncology. It is not surprising that the study of the tumor microenvironment is now considered to be as important as the study of tumor cells. Recent advances in technological and analytical methods, especially ‘omics’ technologies, has made it possible to identify specific targets in tumor cells and within the tumor microenvironment to eradicate cancer. Tumors need constant support from previously ‘unsupportive’ microenvironments. Novel therapeutic strategies that inhibit such microenvironmental support to tumor cells would reduce chemoresistance and tumor relapse. Such strategies can target stromal cells, proteins released by stromal cells and non-cellular components such as the extracellular matrix (ECM) within the tumor microenvironment. Novel in vitro tumor biology models that recapitulate the in vivo tumor microenvironment such as multicellular tumor spheroids, biomimetic scaffolds and tumor organoids are being developed and are increasing our understanding of cancer cell-microenvironment interactions. This review offers an analysis of recent developments on the role of the tumor microenvironment in the development of chemoresistance and the strategies to overcome microenvironment-mediated chemoresistance. We propose a systematic analysis of the relationship between tumor cells and their respective tumor microenvironments and our data show that, to survive, cancer cells interact closely with tumor microenvironment components such as mesenchymal stem cells and the extracellular matrix.

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Section: Strategies To Overcome Chemoresistancementioning

confidence: 99%

The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer

Senthebane

Rowe

Thomford

et al. 2017

IJMS

334

330

View full text Add to dashboard Cite

show abstract

“…For example, pO 2 is 24 mmHg in the brain, 24 mmHg in the liver, 66 mmHg in the spleen, and 25 mmHg in the kidney ( 4 ). During oncogenesis and development of solid tumors, the microenvironment is in a state of significant hypoxia ( 5 ). Hyperoxia is used to describe am increase in oxygen or partial oxygen critical values, whereas hypoxia describes their decrease ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

Conversion of epithelial-to-mesenchymal transition to mesenchymal-to-epithelial transition is mediated by oxygen concentration in pancreatic cancer cells

Chen

et al. 2018

Oncol Lett

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Tumor metastasis is accompanied by a two-stage process of epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET). Currently, the exact mechanisms underlying EMT-MET conversion are unclear. In the present study, the mechanisms by which primary sites (hypoxic) and homing sites (normoxic or hyperoxic) participate in EMT-MET conversion were evaluated. Pancreatic cancer cells were grown under different oxygenation conditions. Cell morphology and epithelial (E)-cadherin and vimentin expression were examined. Transwell chambers were used to examine tumor invasiveness, and scratch assays were performed to examine cell migration. Reverse transcription-polymerase chain reaction and western blot analysis were used to quantitate the mRNA and protein expression of E-cadherin, vimentin, Snail and hypoxia-inducible factor (HIF)-1α. BxPc-3 and Panc-1 cells grown under hypoxic conditions demonstrated increased partial EMT, reduced E-cadherin expression, and increased vimentin expression, compared with cells grown under normoxic or hyperoxic conditions. Cells grown under hypoxic conditions also indicated increased migration and invasiveness. HIF-1α mRNA and protein expression was increased in cells grown under hypoxic conditions. These changes were reversed when a specific inhibitor of the HIF-1α receptor was used to block HIF-1α signaling. Differences in oxygen concentration at primary sites and homing sites are important in the EMT-MET process, and the underlying mechanism may involve HIF-1α-Snail signaling.

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“…Enzyme–substrate recognition between deoxycytidine kinase and GEM relies on hydrogen bonding between the 4‐NH 2 group of the nucleobase cytosine and Asp133, located in the active site of the enzyme . Chemically and enzymatically activatable GEM prodrugs have been developed by installing a protecting group onto the 4‐NH 2 group . Thus, A‐GEM was also designed by masking the same position in GEM with a boronate‐ester‐based carbamate protecting group (Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…Recent studies suggest that targeting unique biochemical alterations in cancer cells is a feasible approach to achieve both therapeutic activity and selectivity . ROS homeostasis is important for the survival and progression of both normal and cancerous cells.…”

Section: Discussionmentioning

confidence: 99%

A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma

et al. 2019

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The main concern in the use of anticancer chemotherapeutic drugs is host toxicity. Patients need to interrupt or change chemotherapy due to adverse effects. In this study, we aimed to decrease adverse events with gemcitabine (GEM) in the treatment of pancreatic ductal adenocarcinoma and focused on the difference of hydrogen peroxide levels in normal versus cancer cells. We designed and synthesized a novel boronate‐ester‐caged prodrug that is activated by the high H2O2 concentrations found in cancer cells to release GEM. An H2O2‐activatable GEM (A‐GEM) has higher selectivity for H2O2 over other reactive oxygen species (ROS) and cytotoxic effects corresponding to the H2O2 concentration in vitro. A xenograft model of immunodeficient mice indicated that the effect of A‐GEM was not inferior to that of GEM when administered in vivo. In particular, myelosuppression was significantly decreased following A‐GEM treatment compared with that following GEM treatment.

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Targeting and Treatment of Tumor Hypoxia by Newly Designed Prodrug Possessing High Permeability in Solid Tumors

Cited by 40 publications

References 20 publications

The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer

The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer

Conversion of epithelial-to-mesenchymal transition to mesenchymal-to-epithelial transition is mediated by oxygen concentration in pancreatic cancer cells

A Hydrogen Peroxide Activatable Gemcitabine Prodrug for the Selective Treatment of Pancreatic Ductal Adenocarcinoma

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