Hypoxia Induces Paclitaxel-Resistance through ROS Production

Oh, Jin-Mi; Ryu, Yun-Kyoung; Lim, Jong‐Seok; Moon, Eun‐Yi

doi:10.4062/biomolther.2010.18.2.145

Cited by 12 publications

(9 citation statements)

References 33 publications

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“…factor, HIF-1α that is stabilized by hypoxia-induced ROS production (Park et al , 2007; Oh et al , 2010). ROS influence intracellular signaling processes which in turn regulate various biological activities such as the motility of cancer cells (Shim et al , 2006; Luanpitpongm et al , 2010; Tobar et al , 2010; Chetram et al , 2011; Lei et al , 2011).…”

Section: Discussionmentioning

confidence: 99%

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Mouse Melanoma Cell Migration is Dependent on Production of Reactive Oxygen Species under Normoxia Condition

Im¹,

Ryu²,

Moon³

2012

Biomolecules and Therapeutics

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Cell migration plays a role in many physiological and pathological processes. Reactive oxygen species (ROS) produced in mammalian cells influence intracellular signaling processes which in turn regulate various biological activities. Here, we investigated whether melanoma cell migration could be controlled by ROS production under normoxia condition. Cell migration was measured by wound healing assay after scratching confluent monolayer of B16F10 mouse melanoma cells. Cell migration was enhanced over 12 h after scratching cells. In addition, we found that ROS production was increased by scratching cells. ERK phosphorylation was also increased by scratching cells but it was decreased by the treatment with ROS scavengers, N-acetylcysteine (NAC). Tumor cell migration was inhibited by the treatment with PD98059, ERK inhibitor, NAC or DPI, well-known ROS scavengers. Tumor cell growth as judged by succinate dehydrogenase activity was inhibited by NAC treatment. When mice were intraperitoneally administered with NAC, the intracellular ROS production was reduced in peripheral blood mononuclear cells. In addition, B16F10 tumor growth was significantly inhibited by in vivo treatment with NAC. Collectively, these findings suggest that tumor cell migration and growth could be controlled by ROS production and its downstream signaling pathways, in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

“…Hypoxic condition enhances prostate and breast cancer cell migration (Jiang et al , 2006; Lin et al , 2009) through the sequential induction of HIF-1α and VEGF (Park et al , 2007). HIF-1α is stabilized by reactive oxygen species (ROS) produced in hypoxic condition (Oh et al , 2010).…”

Section: Introductionmentioning

confidence: 99%

Mouse Melanoma Cell Migration is Dependent on Production of Reactive Oxygen Species under Normoxia Condition

Im¹,

Ryu²,

Moon³

2012

Biomolecules and Therapeutics

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“…Tβ4 can also depolymerize F‐actin, which support the idea that it has multiple, seemingly diverse, cellular functions 5, 6. Tβ4 plays a role in antiapoptosis to an external stress,7 paclitaxel‐resistance through ROS production8–11 and HIF‐1α stabilization through extracellular signal‐regulated kinase (ERK) activation 12. In addition, Tβ4 is a hypoxia‐responsive regulator to control cancer cell migration in angiogenesis and tumor metastasis 1, 13, 14.…”

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confidence: 99%

Regulation of glycogen synthase kinase‐3 by thymosin beta‐4 is associated with gastric cancer cell migration

Ryu

Lee

et al. 2012

Intl Journal of Cancer

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Thymosin beta-4 (Tb4), actin-sequestering protein, plays important roles in many cellular functions including cancer cell migrations. Glycogen synthase kinase (GSK) in Wnt signaling pathway is a key molecule to control intercellular interaction. Here, we investigated whether GSK-3 activity is regulated by Tb4 and it is associated with Tb4-mediated migration in gastric cancer cells. Various expression level of Tb4 was observed in human gastric tumor tissues. Migration in gastric cancer cells, SNU638 and SNU668, was dependent on a relative expression level of Tb4. Cell migration was higher in SNU668 with a higher expression level of Tb4 than that in SNU638 with a lower Tb4. Although the level of phosphorylated(p)-GSK-3a (inactive), b-catenin, E-cadherin and E-cadherin:b-catenin complex was relatively higher, p-GSK-3b (inactive) was lower in SNU638 compared to those in SNU668 cells. LiCl, GSK-3a/b inhibitor, reduced lung metastasis of B16F10 mouse melanoma cells and SNU668 cell migration. Small interference (si)RNA of GSK-3a increased SNU638 cell migration in accordance with the reduction of E-cadherin:b-catenin complex formation through a decrease in b-catenin and E-cadherin. Expression level of GSK-3a/b, b-catenin and E-cadherin in SNU668 and SNU638 was reversed by Tb4-siRNA and by the treatment with acetylatedserine-aspartic acid-lysine-proline (SDKP) tetrapeptide of Tb4, respectively. E-cadherin expression in SNU638 cells was decreased by b-catenin-siRNA. PD98059, MEK inhibitor, or U0126, ERK inhibitor, reduced SNU668 cell migration accompanying an increase in p-GSK-3a, b-catenin and E-cadherin. Taken together, data indicated that the expression of GSK3a, b-catenin and E-cadherin could be negatively regulated by Tb4-induced ERK phosphorylation. It suggests that Tb4 could be a novel regulator to control Wnt signaling pathways.When cancer cells are away from the original place to the secondary location, cancer cell transition happens by the course of cell migration and adhesion in which a wide variety of proteins are involved and form a complex structure accompanying the reorganization of actin cytoskeleton. Thymosin beta-4 (Tb4) proteins regulate intracellular signal transduction and cytoskeleton structure.Tb4 initially isolated from the thymus in 1981 is a small and naturally occurring 43-amino acid peptide present in all cells except erythrocytes. Tb4 is one of b-thymosins that are the most abundant member of highly conserved polar 5-kDa peptides.

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“…Chemoresistance of solid tumors has been attributed to pharmacokinetic as well as other microenvironmental factors (2,3,25). Distribution of many anticancer drugs within tumors was shown to be poor and heterogeneous.…”

Section: Discussionmentioning

confidence: 99%

Penetration of paclitaxel and 5-fluorouracil in multicellular layers of human colorectal cancer cells

Choi

Kim²,

Kuh

2011

Oncol Rep

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Abstract. Limited efficacy of chemotherapeutic drugs against solid tumors has been attributed to poor drug penetration into tumor tissues. Multicellular layer (MCL) cultures recapitulate barriers to drug penetration and distribution and have been used successfully in the production of clinically relevant data. In the present study, we evaluated the characteristics of paclitaxel (PTX) and 5-fluorouracil (5-FU) penetration and their effects on tissue penetration using MCLs of human colorectal cancer cells (DLD-1 and HT-29) grown in Transwell inserts. Drug concentration in conditioned media after MCL penetration was estimated using % survival of cells exposed to the conditioned media, and the penetration rate was calculated as % drug concentration relative to the expected concentration after penetration of cell-free MCLs. PTX showed limited penetration in both MCLs in contrast to the full penetration seen by 5-FU. The penetration rate measured after 24 h by cytotoxicity of the conditioned media was 40 and 38% in DLD-1 (20 μM) and HT-29 MCLs (1 μM), respectively, at which concentration the conditioned media produced 50% growth inhibition in monolayers. The penetration profile obtained using [14 C]-paclitaxel also showed slow and limited penetration with concentration-and cell line-dependency. In HT-29 MCL, full penetration of PTX was obtained at 10 μM after 48 h, whereas only 80% was obtained at 1 μM. In DLD-1 MCLs, penetration of PTX was minimal, especially at 1 μM, showing penetration rates as low as 10 and 20% after 24 and 96 h, respectively. When PTX and 5-FU were allowed to penetrate in sequential combination, no effect on the penetration rate was observed. Overall, our results demonstrated limited penetration of PTX in human colorectal cancer MCLs along with concentration-, time-, and cell line-dependency. Assessment of penetration using cytotoxicity of the conditioned media used in the present study may be useful in early stage screening of anticancer agents for their potential in tissue penetration.

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Hypoxia Induces Paclitaxel-Resistance through ROS Production

Cited by 12 publications

References 33 publications

Mouse Melanoma Cell Migration is Dependent on Production of Reactive Oxygen Species under Normoxia Condition

Mouse Melanoma Cell Migration is Dependent on Production of Reactive Oxygen Species under Normoxia Condition

Regulation of glycogen synthase kinase‐3 by thymosin beta‐4 is associated with gastric cancer cell migration

Penetration of paclitaxel and 5-fluorouracil in multicellular layers of human colorectal cancer cells

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