The BH3-mimetic obatoclax reduces HIF-1α levels and HIF-1 transcriptional activity and sensitizes hypoxic colon adenocarcinoma cells to 5-fluorouracil

Gariboldi, Marzia Bruna; Taìana, Elisa; Bonzi, M. C.; Craparotta, Ilaria; Giovannardi, Stefano; Mancini, Monica; Monti, Elena

doi:10.1016/j.canlet.2015.05.008

Cited by 24 publications

(20 citation statements)

References 46 publications

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“…The importance of PHD levels in HIF1α and HIF2α ubiquitination have also been suggested. Nevertheless, we did not observe significant difference in VHL levels in IL‐6si/sc cell sets following cisplatin treatment, and this observation is consistent with a recent report suggesting the VHL‐independent proteasomal degradation of HIF in colon cancer cells . We speculate that the suppressed PHDs in IL‐6‐expressing sc cells, in turn, suppressed HIF ubiquitination following cisplatin treatment, and consequently the HIF molecules may be protected from degradation.…”

Section: Discussionsupporting

confidence: 92%

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

et al. 2016

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Cisplatin‐resistant A549 and H157 (A549CisR and H157CisR) non‐small cell lung cancer cells show increased stemness of cancer stem cells (CSCs) compared to their parental cells. We investigated whether interleukin‐6 (IL‐6) signaling contributes to this increased stemness in cisplatin‐resistant cells. When A549CisR and H157CisR cells were treated with neutralizing IL‐6 antibody, decreased cisplatin resistance was observed, whereas IL‐6 treatment of parental cells resulted in increased cisplatin resistance. Expression of the CSC markers was significantly upregulated in IL‐6‐expressing scramble cells (in vitro) and scramble cell‐derived tumor tissues (in vivo) after cisplatin treatment, but not in IL‐6 knocked down (IL‐6si) (in vitro) cells and in IL‐6si cell‐derived tumor tissues (in vivo), suggesting the importance of IL‐6 signaling in triggering increased stemness during cisplatin resistance development. Hypoxia inducible factors (HIFs) were upregulated by IL‐6 and responsible for the increased CSC stemness on cisplatin treatment. Mechanism dissection studies found that upregulation of HIFs by IL‐6 was through transcriptional control and inhibition of HIF degradation. Treatment of HIF inhibitor (FM19G11) abolished the upregulation of CSC markers and increased sphere formations in IL‐6 expressing cells on cisplatin treatment. In all, IL‐6‐mediated HIF upregulation is important in increasing stemness during cisplatin resistance development, and we suggest that the strategies of inhibiting IL‐6 signaling or its downstream HIF molecules can be used as future therapeutic approaches to target CSCs after cisplatin treatment for lung cancer.

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Section: Discussionsupporting

confidence: 92%

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

et al. 2016

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“…Hu et al uncovered that the autophagy inhibitor chloroquine made autophagic cell death shift to apoptotic cell death in vitro in hypoxic cells [ 81 ]. Additionally, the BH3 mimetic obatoclax sensitizes hypoxic colon adenocarcinoma cells to 5-fluorouracil [ 82 ].…”

Section: Cell Fate Decision Under Hypoxia and Tumor Therapy Implicmentioning

confidence: 99%

Cell Death Conversion under Hypoxic Condition in Tumor Development and Therapy

Qiu

Peng

2015

IJMS

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Hypoxia, which is common during tumor progression, plays important roles in tumor biology. Failure in cell death in response to hypoxia contributes to progression and metastasis of tumors. On the one hand, the metabolic and oxidative stress following hypoxia could lead to cell death by triggering signal cascades, like LKB1/AMPK, PI3K/AKT/mTOR, and altering the levels of effective components, such as the Bcl-2 family, Atg and p62. On the other hand, hypoxia-induced autophagy can serve as a mechanism to turn over nutrients, so as to mitigate the adverse condition and then avoid cell death potentially. Due to the effective role of hypoxia, this review focuses on the crosstalk in cell death under hypoxia in tumor progression. Additionally, the illumination of cell death in hypoxia could shed light on the clinical applications of cell death targeted therapy.

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“…Other studies have demonstrated that the BH3 analogue ABT-737 was able to exert its effect on tumor cells more efficiently under hypoxic conditions compared with cells treated in normoxic conditions (31,32). OBX was reported to reduce the expression level of HIF-1α under hypoxic conditions, thereby enhancing the sensitivity of colon cancer cells to 5-fluorouracil treatment (33). However, whether OBX combined with GEM was able to change the invasive phenotype of BxPC-3 pancreatic cancer cells under hypoxic conditions and improve the efficiency of GEM treatment remained unreported.…”

Section: Discussionmentioning

confidence: 99%

Effects of obatoclax combined with gemcitabine on the biological activity of pancreatic cancer cells under hypoxic conditions

Hou

et al. 2018

Mol Med Report

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The present study aimed to investigate the effects of obatoclax (OBX) combined with gemcitabine (GEM) treatment on the proliferation, migration, invasion and epithelial‑mesenchymal transition (EMT) related proteins of pancreatic cancer cell line BxPC‑3 under hypoxic conditions. Protein expression levels of hypoxia‑inducible factor 1α (HIF‑1α) in BxPC‑3 pancreatic cancer cells under normoxic and hypoxic conditions were detected by western blotting. Cells were divided into four groups: Normoxia group, hypoxia group, OBX group and OBX + GEM group. The proliferation activity of BxPC‑3 cells was detected by Cell Counting kit‑8. The migratory and invasive abilities of BxPC‑3 cells were detected by the scratch test and Matrigel assay, respectively. The protein expression levels of vimentin, E‑cadherin and p53 in BxPC‑3 cells were also detected by western blotting. HIF‑1α expression under hypoxic conditions was significantly increased compared with expression under normoxic conditions. Under hypoxic conditions, OBX treatment reduced cell activity, decreased cell migration and invasion, promoted the expression of E‑cadherin and p53. In the OBX + GEM group, BxPC‑3 cell activity decreased significantly, cell migration and invasion decreased significantly, the expression of vimentin was significantly reduced and the expression of E‑cadherin and p53 further increased. In conclusion, the present results demonstrated that under hypoxic conditions, OBX combined with a small dose of GEM may be able to inhibit the growth, migration and invasion of pancreatic cancer cells, possibly via inhibition of EMT process. These results may provide a promising strategy for pancreatic cancer therapy.

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The BH3-mimetic obatoclax reduces HIF-1α levels and HIF-1 transcriptional activity and sensitizes hypoxic colon adenocarcinoma cells to 5-fluorouracil

Cited by 24 publications

References 46 publications

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

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

Cell Death Conversion under Hypoxic Condition in Tumor Development and Therapy

Effects of obatoclax combined with gemcitabine on the biological activity of pancreatic cancer cells under hypoxic conditions

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