Tumor Hypoxia, Drug Resistance, and Metastases

Jm, Brown

doi:10.1093/jnci/82.5.338

Cited by 75 publications

(40 citation statements)

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“…We also found that hypoxia induces drug resistance to etoposide, melphalan, doxorubicin, and cyclophosphamide in neuroblastoma cells, which is mediated through an expanded autocrine loop between VEGF/Flt1 and HIF-1a expression (8). There is evidence that some cells in hypoxic regions remain alive in a dormant state for prolonged duration and become drug resistant as anticancer drugs preferentially target rapidly proliferating cells (6). Hypoxia-inducible factors also induce stem cell phenotype and suppress differentiation of neuroblastoma cells (9).…”

Section: Introductionmentioning

confidence: 81%

“…Hypoxia can be a direct cause of therapeutic resistance due to limited blood supply and drug distribution (5). Hypoxia also inhibits tumor cell proliferation and induces cell-cycle arrest, further enhancing chemoresistance through regulating drug transporters, antiapoptotic proteins, and proangiogenic factors (6). Our previous studies have shown that tumor hypoxic microenvironment may serve as a niche for the highly tumorigenic fraction of tumor cells which exhibit the cancer stem cell features in a diverse group of solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, and smallcell lung carcinoma (7).…”

Section: Introductionmentioning

confidence: 99%

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Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models

Zhang

Marrano

et al. 2016

Clinical Cancer Research

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Purpose: Tumor cells residing in tumor hypoxic zones are a major cause of drug resistance and tumor relapse. In this study, we investigated the efficacy of evofosfamide, a hypoxia-activated prodrug, and its combination with topotecan in neuroblastoma and rhabdomyosarcoma preclinical models.Experimental Design: Neuroblastoma and rhabdomyosarcoma cells were tested in vitro to assess the effect of evofosfamide on cell proliferation, both as a single agent and in combination with topotecan. In vivo antitumor activity was evaluated in different xenograft models. Animal survival was studied with the neuroblastoma metastatic tumor model.Results: All tested cell lines showed response to evofosfamide under normoxic conditions, but when exposed to hypoxia overnight, a 2-to 65-fold decrease of IC 50 was observed. Adding topotecan to the evofosfamide treatment significantly increased cytotoxicity in vitro. In neuroblastoma xenograft models, single-agent evofosfamide treatment delayed tumor growth. Complete tumor regression was observed in the combined topotecan/evofosfamide treatment group after 2-week treatment. Combined treatment also improved survival in a neuroblastoma metastatic model, compared to singleagent treatments. In rhabdomyosarcoma xenograft models, combined treatment was more effective than single agents. We also showed that evofosfamide mostly targeted tumor cells within hypoxic regions while topotecan was more effective to tumor cells in normoxic regions. Combined treatment induced tumor cell apoptosis in both normoxic and hypoxic regions.Conclusions: Evofosfamide shows antitumor effects in neuroblastoma and rhabdomyosarcoma xenografts. Compared with single-agent, evofosfamide/topotecan, combined therapy improves tumor response, delays tumor relapse, and enhances animal survival in preclinical tumor models. Clin Cancer Res; 22(11); 2697-708. Ó2015 AACR.

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Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models

Zhang

Marrano

et al. 2016

Clinical Cancer Research

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“…Therefore, the lower survival of PERK Ϫ/Ϫ cells following exposure to hypoxia is not due to slower growth of these cells but reflects the lower number of cells that survive the stress to form colonies, compared with that of PERK ϩ/ϩ cells DISCUSSION Cellular adaptation to hypoxic stress is a multifaceted process that involves both a shift of cellular metabolism toward anaerobic glycolysis and an inhibition of energy-consuming processes like cell proliferation and macromolecular synthesis (30,54,57,70). At the multicellular or organ level, additional mechanisms like neoangiogenesis and increased synthesis of erythropoietin are also employed in an attempt to increase the oxygen supply to oxygen-starved tissue (4,58,59). Abnormalities in oxygen homeostasis are associated with pathological disease states, including brain and cardiac muscle ischemiareperfusion injury and tumor hypoxia (2,14,18,46,73).…”

Section: Perk a Kinase That Phosphorylates Eif2␣ In Response To Er Smentioning

confidence: 99%

Regulation of Protein Synthesis by Hypoxia via Activation of the Endoplasmic Reticulum Kinase PERK and Phosphorylation of the Translation Initiation Factor eIF2α

Koumenis

Naczki

Koritzinsky

et al. 2002

Molecular and Cellular Biology

635

564

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Hypoxia profoundly influences tumor development and response to therapy. While progress has been made in identifying individual gene products whose synthesis is altered under hypoxia, little is known about the mechanism by which hypoxia induces a global downregulation of protein synthesis. A critical step in the regulation of protein synthesis in response to stress is the phosphorylation of translation initiation factor eIF2␣ on Ser51, which leads to inhibition of new protein synthesis. Here we report that exposure of human diploid fibroblasts and transformed cells to hypoxia led to phosphorylation of eIF2␣, a modification that was readily reversed upon reoxygenation. Expression of a transdominant, nonphosphorylatable mutant allele of eIF2␣ attenuated the repression of protein synthesis under hypoxia. The endoplasmic reticulum (ER)-resident eIF2␣ kinase PERK was hyperphosphorylated upon hypoxic stress, and overexpression of wild-type PERK increased the levels of hypoxia-induced phosphorylation of eIF2␣. Cells stably expressing a dominant-negative PERK allele and mouse embryonic fibroblasts with a homozygous deletion of PERK exhibited attenuated phosphorylation of eIF2␣ and reduced inhibition of protein synthesis in response to hypoxia. PERK ؊/؊ mouse embryo fibroblasts failed to phosphorylate eIF2␣ and exhibited lower survival after prolonged exposure to hypoxia than did wild-type fibroblasts. These results indicate that adaptation of cells to hypoxic stress requires activation of PERK and phosphorylation of eIF2␣ and suggest that the mechanism of hypoxia-induced translational attenuation may be linked to ER stress and the unfolded-protein response.Tumor hypoxia is a well-characterized feature of the solidtumor microenvironment. The development of hypoxia has profound consequences on tumor growth characteristics and on tumor response to radiotherapy and chemotherapy. Hypoxic tumors are more metastatic, are more resistant to radiotherapy and chemotherapy, and have a poorer prognosis than better-oxygenated ones, irrespective of therapy (28,29,72). Delineating the mechanisms by which hypoxia affects tumor physiology at the cellular and molecular levels is crucial for a better understanding of the process of tumor development and metastasis and for the design of better antitumor modalities.At the cellular level, exposure of cells to hypoxia has an immediate and reversible effect on proliferation. In Ehrlich ascites and HeLa cells, replicons stop firing within minutes of exposure to hypoxia, resulting in a G 1 /S-phase arrest. Upon reoxygenation, replicons begin extending, again within minutes (50-52). This hypoxia-induced G 1 /S arrest is independent of functional p53 tumor suppressor protein, since cells with mutant p53 and p53 knockout cells also arrest at the G 1 /S interface under hypoxic conditions (22). These studies point toward a unique mechanism of checkpoint control that differs from those induced by glucose deprivation or ionizing radiation, which require considerably more time for reinitiation of the cel...

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“…The outer regions of tumors tend to be highly vascularized, but these blood vessels are unorganized and discontinuous, resulting in high permeability and "leakiness"; a phenomena that is exploited in passively targeted delivery and referred to as the enhanced permeability and retention (EPR) effect [20,21]. Due to the diffusion limit of oxygen, tumor cells that are more than 100 −150 μm from blood vessels tend to be oxygen deprived, leading to chronic hypoxia and inevitable necrosis [22,23]. Acute hypoxic regions can also be created when blood vessels are closed, which often occurs in the microenvironment of a tumor due to compression, tumor cell invasion, and discontinuity of the epithelial cells lining the vessels [20,23].…”

Section: Tumor Microenvironment and Mdrmentioning

confidence: 99%

“…Hypoxia in cancer has been associated with increased metastatic potential, increased drug resistance, and poor prognosis [20,22,23,[29][30][31][32]. A study conducted in the 1990's on 37 patients with cervical cancer monitored intra-tumor oxygen levels, apoptotic index, and metastasis and found that hypoxic apoptotic-resistant tumors resulted in higher degrees of metastasis compared to apoptotic sensitive hypoxic tumors and non-hypoxic tumors [30].…”

Section: Tumor Microenvironment and Mdrmentioning

confidence: 99%

Multi-functional nanocarriers to overcome tumor drug resistance

Jabr-Milane¹,

Vlerken²,

Yadav³

et al. 2008

Cancer Treatment Reviews

379

251

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The development of resistance to variety of chemotherapeutic agents is one of the major challenges in effective cancer treatment. Tumor cells are able to generate a multi-drug resistance (MDR) phenotype due to microenvironmental selection pressures. This review addresses the use of nanotechnology-based delivery systems to overcome MDR in solid tumors. Our own work along with evidence from the literature illustrates the development of various types of engineered nanocarriers specifically designed to enhance tumor-targeted delivery through passive and active targeting strategies. Additionally, multi-functional nanocarriers are developed to enhance drug delivery and overcome MDR by either simultaneous or sequential delivery of resistance modulators (e.g., with P-glycoprotein substrates), agents that regulate intracellular pH, agents that lower the apoptotic threshold (e.g., with ceramide), or in combination with energy delivery (e.g., sound, heat, and light) to enhance the effectiveness of anticancer agents in refractory tumors. In preclinical studies, the use of multi-functional nanocarriers has shown significant promise in enhancing cancer therapy, especially against MDR tumors.

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Tumor Hypoxia, Drug Resistance, and Metastases

Cited by 75 publications

References 0 publications

Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models

Combined Antitumor Therapy with Metronomic Topotecan and Hypoxia-Activated Prodrug, Evofosfamide, in Neuroblastoma and Rhabdomyosarcoma Preclinical Models

Regulation of Protein Synthesis by Hypoxia via Activation of the Endoplasmic Reticulum Kinase PERK and Phosphorylation of the Translation Initiation Factor eIF2α

Multi-functional nanocarriers to overcome tumor drug resistance

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