Cisplatin treatment increases stemness through upregulation of hypoxia‐inducible factors by interleukin‐6 in non‐small cell lung cancer

Zhang, Fuquan; Duan, Shanzhou; Tsai, Ying Huang; Keng, Peter C.; Chen, Yongbing; Lee, Soo Ok; Chen, Yuhchyau

doi:10.1111/cas.12937

Cited by 48 publications

(43 citation statements)

References 42 publications

(68 reference statements)

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“…Consistent with previous reports, after chemotherapy with DOX, TNF-a and IL-6 was upregulated in the tumour through NF-jB pathway, which promotes tumour cells survival [34,35] and lead to therapeutic resistance. After conventional chemotherapy with DOX, TNF-a (green fluorescence) and IL-6 (red fluorescence) was upregulated in the tumour, which is consistent with the study of Dash et al [36] and Zhang et al [37]. As shown in Figure 7(B,C), protein expressions of TNF-a and IL-6 in the tumour of the mice treated with RBC@BPQDs-DOX/KIR was significantly decreased at the end of the observation compared with those in the control group (p< .01).…”

Section: Anti-inflammatory Activity In Vivosupporting

confidence: 90%

Anti-tumour effects of red blood cell membrane-camouflaged black phosphorous quantum dots combined with chemotherapy and anti-inflammatory therapy

Huang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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2019) Anti-tumour effects of red blood cell membrane-camouflaged black phosphorous quantum dots combined with chemotherapy and anti-inflammatory therapy, Artificial Cells, Nanomedicine, and Biotechnology, 47:1, 968-979, ABSTRACTConventional anti-tumour chemotherapy is facing the challenges of poor specificity, high toxicity and drug resistance. Tumour microenvironment (TME) plays a critical role in tumour development and drug resistance. To address this problem, we constructed a novel anti-tumour nanoparticle platform RBC@BPQDs-DOX/KIR, black phosphorus nanoparticle quantum dots (BPQDs) with one of the chemotherapeutics (doxorubicin, DOX) and an anti-inflammatory traditional Chinese medicine active component (Kirenol, KIR). Red blood cell membrane (RBCm) vesicles were used as the shell to envelop several nanocores. The combination of DOX and KIR may promote therapeutic efficacy, at which the anti-apoptotic effect of the tumour cells was inhibited (by downregulating Bcl-2 and upregulating Bax) and the tumour progression-related inflammatory factors, such as tumour necrosis factor a (TNF-a) and interleukin-6 (IL-6) were downregulated. Furthermore, TME was remodelled and the anti-tumour effect of DOX was magnified. RBCm imparts high biocompatibility and enhanced permeability and retention (EPR) effects to RBC@BPQDs-DOX/KIR, thus enhancing its tumour passively targetability. Overall, the RBCmcamouflaged drug delivery system RBC@BPQDs-DOX/KIR as a promising therapy for targeted chemotherapeutics and anti-inflammatory therapeutics may provide a specific and highly efficient anti-tumour treatment choice. ARTICLE HISTORY

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Section: Anti-inflammatory Activity In Vivosupporting

confidence: 90%

Anti-tumour effects of red blood cell membrane-camouflaged black phosphorous quantum dots combined with chemotherapy and anti-inflammatory therapy

Huang

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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“…However, IL-6 has also been found to alter the susceptibility of tumor cells to apoptosis by chemotherapeutic drugs [ 37 ]. Results from a recent study have revealed that IL-6 treatment was found to be associated with increased cisplatin resistance in lung CSC and increased CSC stemness [ 27 ]. When lung CSC were treated with neutralizing IL-6 antibody, cisplatin resistance decreased [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Findings from recent studies have indicated that the expressions of CSC markers are significantly upregulated in IL-6 expressing lung cancer cells and cell-derived tumor xenograft tissues after cisplatin treatment. However, these CSC markers were not upregulated in IL-6 knockdown cells and in IL-6 knockdown cell-derived tumor tissue [ 27 ]. Negative effects of IL-6 signaling in triggering increased tumor growth and drug resistance in lung cancer during cisplatin treatment have been reported [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Ribonucleic acid interference knockdown of IL-6 enhances the efficacy of cisplatin in laryngeal cancer stem cells by down-regulating the IL-6/STAT3/HIF1 pathway

Pengruofeng

Sun

et al. 2017

Cancer Cell Int

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BackgroundCisplatin has been used in the treatment of many cancers, including laryngeal cancer; however, its efficacy can be reduced due to the development of drug resistance. This study aimed to investigate whether interleukin-6 (IL-6) knockdown may enhance the efficacy of cisplatin in laryngeal cancer stem cells (CSC) and the potential involvement of the signal transducer and activator of transcription 3 (STAT3) and hypoxia-inducible factor 1 (HIF1) in this effect.MethodsThe ALDH+ and CD44+ CSC in Hep2 human laryngeal squamous cancer cells were identified by the fluorescence-activated cell sorting technique. IL-6, STAT3 and HIF1 mRNA and protein expressions were examined with quantitative real-time polymerase chain reaction and Western blot, respectively. Cell proliferation was measured by MTT assay. Tumorigenicity was measured by a colony formation assay and invasion was determined by a cell invasion assay. Apoptotic cells were counted by flow cytometry. Immunohistochemistry was performed to detect immunoreactive IL-6, STAT3 and HIF1 cells in xenografts.ResultsThe mRNA and protein levels of IL-6, STAT3 and HIF1 were significantly increased in Hep2-CSC as compared with those from Hep2 cells. Application of siRNA-IL-6 to knockdown IL-6 resulted in significantly decreased IL-6, STAT3 and HIF1 mRNA and protein levels. IL-6 knockdown reduced cell proliferation, tumorigenicity and invasion and increased apoptosis within CSC. Enhanced degrees of suppression in these parameters were observed when IL-6 knockdown was combined with cisplatin in these CSC. Results from the xenograft study showed that the combination of IL-6 knockdown and cisplatin further inhibited the growth of xenografts as compared with that obtained in the cisplatin-injected group alone. Immunoreactive IL-6, STAT3 and HIF1 cell numbers were markedly reduced in IL-6 knockdown tumor tissues. IL-6, STAT3 and HIF1 immunoreactive cell counts were further reduced in tissue where IL-6 knockdown was combined with cisplatin treatment as compared with tissue receiving cisplatin alone.ConclusionsIL-6 knockdown can increase chemo-drug efficacy of cisplatin, inhibit tumor growth and reduce the potential for tumor recurrence and metastasis in laryngeal cancer. The IL-6/STAT3/HIF1 pathway may represent an important target for investigating therapeutic strategies for the treatment of laryngeal cancer.

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“…IL-6 is one of the main chemokines present in serum samples of head and neck cancer patients and elevated IL-6 levels independently predict tumor recurrence, poor survival and tumor metastasis [18]. The tumorpromoting activities of IL-6 are manifold and include the evasion of growth suppression by regulating the TP53 gene [19], mediating resistance against cell death [20,21], increasing stemness of tumor cells [22,23], and mediating tumor invasion and metastasis through EMT via the JAK/STAT3/Snail signaling pathway [24,25].…”

Section: Introductionmentioning

confidence: 99%

Pleiotropic Effects of Epithelial Mesenchymal Crosstalk on Head and Neck Cancer: EMT and beyond

Steinbichler

Savic

Dejaco

et al. 2019

Cancer Microenvironment

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Epithelial mesenchymal crosstalk (EMC) describes the interaction of the tumor stroma and associated fibroblasts with epithelial cancer cells. In this study we analysed the effects of EMC on head and neck cancer cells. In tumor cell lines EMC was induced using media conditioned from a mix-culture of cancer cells and fibroblasts. Cell proliferation and chemotherapy response were assessed using direct cell counting. Flow cytometry, immunohistochemistry of markers of epithelial-mesenchymal transition (EMT) and subsequent TissueFaxs™ acquisition and quantification and western blot analysis were performed. Holotomographic microscopy imaging was used to visualize the effects of EMC on Cisplatin response of SCC-25 cells. EMC induced a hybrid epithelial-mesenchymal phenotype in SCC-25 cells with co-expression of vimentin and cytokeratin. This hybrid phenotype was associated with chemotherapy resistance and increased proliferation of the cells. The EMC conditioned medium led to an activation of the IL-6/STAT3 pathway with subsequent phosphorylation of STAT3. EMC induced a hybrid epithelialmesenchymal phenotype in HNSCC cells accompanied by increased therapy resistance and cell proliferation. The IL-6/ STAT3 pathway might be one of the major pathways involved in these EMC-related effects.

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Cisplatin treatment increases stemness through upregulation of hypoxia‐inducible factors by interleukin‐6 in non‐small cell lung cancer

Cited by 48 publications

References 42 publications

Anti-tumour effects of red blood cell membrane-camouflaged black phosphorous quantum dots combined with chemotherapy and anti-inflammatory therapy

Anti-tumour effects of red blood cell membrane-camouflaged black phosphorous quantum dots combined with chemotherapy and anti-inflammatory therapy

Ribonucleic acid interference knockdown of IL-6 enhances the efficacy of cisplatin in laryngeal cancer stem cells by down-regulating the IL-6/STAT3/HIF1 pathway

Pleiotropic Effects of Epithelial Mesenchymal Crosstalk on Head and Neck Cancer: EMT and beyond

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