Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies

Shannon, Aoife M.; Bouchier‐Hayes, David; Condron, Claire; Toomey, Deirdre

doi:10.1016/s0305-7372(03)00003-3

Cited by 496 publications

(404 citation statements)

References 87 publications

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“…27,28 Furthermore, mechanisms of cisplatin-induced resistance under hypoxia are mainly due to indirect effects, including cell cycle arrest and DNA repair, not the O 2 itself. 29 Much evidence has shown that hypoxia is closely associated with tumor resistance to anticancer drugs, and many factors contribute to the mechanisms. 29 Both direct and indirect factors of hypoxia account for drug resistance.…”

Section: Discussionmentioning

confidence: 99%

“…29 Much evidence has shown that hypoxia is closely associated with tumor resistance to anticancer drugs, and many factors contribute to the mechanisms. 29 Both direct and indirect factors of hypoxia account for drug resistance. Since HIF-1 is one of the major regulators of adaptive response to hypoxia, targeting HIF-1 to reverse Effects of lentivirus-mediated HIF-1a knockdown J Hao et al the hypoxia-related drug resistance has received much interest.…”

Section: Discussionmentioning

confidence: 99%

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Effects of lentivirus-mediated HIF-1α knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells

Hao

Song

et al. 2008

Cancer Gene Ther

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Therapy targeting hypoxia-inducible factor-1 (HIF-1) to reverse the hypoxia-related drug resistance has received much interest. Despite a close interaction between HIF-1 and p53 and that p53 mutation is seen in 450% of tumors, whether HIF-1 silencing by targeted therapy depends on tumor p53 status remains unknown. Two isogenic fibrosarcoma cells HT1080 (wild-type p53) and HT1080-6TG (mutant p53) were transduced with HIF-1a-specific RNAi lentiviral vectors and selected with blasticidin. Real-time PCR and western blot analysis of HIF-1a mRNA and protein respectively validated the silencing effects. Cells were first preconditioned under hypoxia (0.5% O 2 ) for 4 h and then co-treated with cisplatin for another 24 h. MTT was used for assessment of chemosensitivity to cisplatin. Moreover, annexin V and propidium iodide staining was detected on flow cytometry for analysis of cisplatin-induced apoptosis. Furthermore, changes of some Bcl-2 family members were detected on western blotting. Exposure to hypoxia significantly increased resistance to cisplatin than exposure to normoxia. HIF-1a knockdown could reverse hypoxia-related resistance to cisplatin and apoptotic resistance only in HT1080 cells, but had little effect on HT1080-6TG cells. With HIF-1a knockdown, Bid expression was higher in HT1080 than in HT1080-6TG under hypoxia. In summary, HIF-1 targeted therapy to reverse hypoxia-related cisplatin resistance depends on normal p53 status. Changes of Bid expression levels under hypoxia might contribute in part to the differential response to HIF-1a silencing in cells with different p53 status.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of lentivirus-mediated HIF-1α knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells

Hao

Song

et al. 2008

Cancer Gene Ther

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“…Tumour hypoxia and suppression of apoptosis are important drivers of drug (Makin and Dive, 2003;Shannon et al, 2003) and radiotherapy (Saunders et al, 2002) resistance in solid tumours. The transcription factor, hypoxia inducible factor-1 (HIF-1), consists of a and b subunits: the former is ubiquitinated and degraded in normoxia but stabilised in hypoxia; the latter is constitutively expressed independent of oxygen (Semenza, 2003).…”

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confidence: 99%

Reciprocal relationship between expression of hypoxia inducible factor 1α (HIF-1α) and the pro-apoptotic protein Bid in ex vivo colorectal cancer

et al. 2008

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Hypoxia inducible factor 1 (HIF-1) represses the transcription of pro-apoptotic bid in colorectal cancer cells in vitro. To assess the clinical relevance of this observation, HIF-1a and Bid were assessed in serial sections of 39 human colorectal adenocarcinomas by immunohistochemistry. In high HIF-1a nuclear-positive cell subpopulations, there was a significant reduction in Bid expression (ANOVA, P ¼ 0.04). Given the role of Bid in drug-induced apoptosis, these data add impetus to strategies targeting HIF-1 for therapeutic gain.

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“…Accumulated data have shown that many factors, including hypoxia, DNA repair capacity, cellular detoxification machinery, etc., are responsible for cancer cells developing drug resistance (1,2). Evidence has indicated that most solid tumors contain hypoxia regions resulting from a poor local vasculature (3). In addition, overexpression of hypoxia-inducible factor-1a (HIF-1a) has been reported in approximately 70% of human tumors compared with their normal adjacent tissues.…”

Section: Introductionmentioning

confidence: 99%

MPT0B098, a Novel Microtubule Inhibitor That Destabilizes the Hypoxia-Inducible Factor-1α mRNA through Decreasing Nuclear–Cytoplasmic Translocation of RNA-Binding Protein HuR

Cheng

Liou

Kuo

et al. 2013

Molecular Cancer Therapeutics

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Microtubule inhibitors have been shown to inhibit hypoxia-inducible factor-1a (HIF-1a) expression through inhibition translation or enhancing protein degradation. Little is known of the effect of microtubule inhibitors on the stability of HIF-1a mRNA. We recently discovered a novel indoline-sulfonamide compound, 7-arylindoline-1-benzene-sulfonamide (MPT0B098), as a potent microtubule inhibitor through binding to the colchicine-binding site of tubulin. MPT0B098 is active against the growth of various human cancer cells, including chemoresistant cells with IC 50 values ranging from 70 to 150 nmol/L. However, normal cells, such as human umbilical vein endothelial cells (HUVEC), exhibit less susceptibility to the inhibitory effect of MPT0B098 with IC 50 of 510 nmol/L. Similar to typical microtubule inhibitors, MPT0B098 arrests cells in the G 2 -M phase and subsequently induces cell apoptosis. In addition, MPT0B098 effectively suppresses VEGFinduced cell migration and capillary-like tube formation of HUVECs. Distinguished from other microtubule inhibitors, MPT0B098 not only inhibited the expression levels of HIF-1a protein but also destabilized HIF-1a mRNA. The mechanism of causing unstable of HIF-1a mRNA by MPT0B098 is through decreasing RNAbinding protein, HuR, translocation from the nucleus to the cytoplasm. Notably, MPT0B098 effectively suppresses tumor growth and microvessel density of tumor specimens in vivo. Taken together, our results provide a novel mechanism of inhibiting HIF-1a of a microtubule inhibitor MPT0B098. MPT0B098 is a promising anticancer drug candidate with potential for the treatment of human malignancies. Mol Cancer Ther; 12(7); 1202-12. Ó2013 AACR.

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Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies

Cited by 496 publications

References 87 publications

Effects of lentivirus-mediated HIF-1α knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells

Effects of lentivirus-mediated HIF-1α knockdown on hypoxia-related cisplatin resistance and their dependence on p53 status in fibrosarcoma cells

Reciprocal relationship between expression of hypoxia inducible factor 1α (HIF-1α) and the pro-apoptotic protein Bid in ex vivo colorectal cancer

MPT0B098, a Novel Microtubule Inhibitor That Destabilizes the Hypoxia-Inducible Factor-1α mRNA through Decreasing Nuclear–Cytoplasmic Translocation of RNA-Binding Protein HuR

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