Strategic targeting of the PI3K–NFκB axis in cisplatin-resistant NSCLC

Heavey, Susan; Godwin, Peter; Baird, Anne‐Marie; Barr, Martin P.; Umezawa, Kazuo; Cuffe, Sinéad; Finn, Stephen P.; O’Byrne, Kenneth J.; Gately, Kathy

doi:10.4161/cbt.29841

Cited by 25 publications

(19 citation statements)

References 31 publications

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“…Constitutive activation of NFκB has been implicated in carcinogenesis and drug resistance in many cancer types. 21 – 23 Therefore, we examined whether this pathway was altered in T24 and T24R cells. Western blotting data revealed that the levels of NFκB/RelA, also known as p65, and its phosphorylated form pRelA (S536) were elevated remarkably in T24R cells, compared to T24 cells.…”

Section: Resultsmentioning

confidence: 99%

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Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells to cisplatin through inhibiting NFκB signaling pathway

Xue

Yang

et al. 2018

OTT

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BackgroundCisplatin-based chemotherapy is mainstay treatment in urinary bladder cancer (UBC). However, tumor recurrence frequently occurs with the acquisition of cisplatin resistance. We explored the potential effect of a polyherbal preparation, Zyflamend, on UBC cells resistant to cisplatin treatment.MethodsTo establish a cisplatin-resistant human bladder cancer cell line, T24 cells were cultured in increasing concentrations of cisplatin for more than 10 months. These cells (T24R) were then treated with different concentrations of Zyflamend, and both proliferation and activity of nuclear factor kappaB (NFκB) signaling pathway were examined. To test the synergistic effect between Zyflamend and cisplatin, we treated T24R cells either with Zyflamend or cisplatin alone, or in combination. Apoptotic effect was evaluated by Annexin V/propidium iodide double staining, and the levels of the proteins involved in cell cycle and anti-apoptosis were examined by Western blotting. Finally, mice with palpable xenograft were treated either with cisplatin and Zyflamend alone or in combination for 28 days before they were sacrificed for measuring the sizes and weights of the tumor tissues. In addition, proliferation and apoptosis markers were examined by immunohistochemistry.ResultsComparing to that in the parental T24 cells, NFκB is constitutively active in cisplatin-resistant T24R cells. Zyflamend is capable of inhibiting the growth of T24, T24R, as well as another UBC cell line J82 in a concentration-dependent manner. Mechanistically, Zyflamend suppresses NFκB-mediated cell proliferation, survival, and invasion/angiogenesis and induces apoptosis. In addition, Zyflamend significantly increased the sensitivity of T24R and J82 cells to cisplatin treatment and these findings were confirmed in T24R xenograft model with reduced proliferation index and decreased expression of RelA and its downstream target MMP9.ConclusionZyflamend is capable of counteracting bladder cancer resistance to cisplatin by repressing proliferation and inducing apoptosis through targeting NFκB signaling pathway.

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Section: Resultsmentioning

confidence: 99%

“…Activation of NFκB has been implicated in chemoresistance of various cancer types, 21 – 23 and cytokine secretion from apoptotic and/or necrotic cancer cells can activate NFκB signaling pathway through paracrine effect. 25 – 27 In addition, cancer cells may also activate NFκB signaling through autocrine secretion of IL-1B.…”

Section: Discussionmentioning

confidence: 99%

Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells to cisplatin through inhibiting NFκB signaling pathway

Xue

Yang

et al. 2018

OTT

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“…Wu et al [ 44 ] suggested using an inhibitor of mTOR signaling to overcome cisplatin-resistance. Heavey et al [ 45 ] reported targeting the PI3K-NFκB pathway for battling cisplatin resistance. In addition, Andriani et al [ 46 ] showed increased sensitivity to cisplatin after applying a FHIT gene into the NSCLC cells, and Bian et al [ 47 ] reported increasing cisplatin sensitivity of NSCLC cells by up-regulation of miRNA451.…”

Section: Discussionmentioning

confidence: 99%

IL-6 signaling contributes to cisplatin resistance in non-small cell lung cancer via the up-regulation of anti-apoptotic and dna repair associated molecules

et al. 2015

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Cisplatin-based chemotherapy is currently the most effective treatment regimen for non-small cell lung cancer (NSCLC), but eventually tumor resistance develops which limits its success. The potential implication of IL-6 signaling in the cisplatin resistance of NSCLC was explored by testing whether NSCLC cells with different levels of intracellular IL-6 show different responses to the cytotoxic treatment of cisplatin. When the cisplatin cytotoxicity of the IL-6 knocked down human NSCLC cells (A549IL-6si and H157IL-6si) were compared with their corresponding scramble control cells (A549sc and H157sc), higher cisplatin cytotoxicity was found in IL-6 si cells than sc cells. Subcutaneous xenograft mouse models were developed using a pair of A549sc and A549IL-6si cells. When the tumor grew to about 400 mm2, mice were treated with cisplatin and tumor regression was monitored. Higher tumor regression was detected in the A549IL-6si xenografts compared to A549sc xenografts following cisplatin treatment. Immunostaining study results from tumor tissues also supported this finding. Expression of anti-apoptotic proteins Bcl-2 and Mcl-1 and DNA repair associated molecules ATM, CHK1, TP73, p53, and ERCC1 were significantly up regulated in cisplatin-treated A549sc and H157sc cells, but no increase was detected in A549IL-6si and H157IL-6si cells. Further inhibitor studies revealed that up regulation of these molecules by IL-6 may be through activation of IL-6 downstream signaling pathways like Akt, MAPK, Stat3, and Erk. These results provide potential for combining cisplatin and inhibitors of IL-6 signaling or its downstream signaling pathway as a future therapeutic approach in preventing development of cisplatin resistant NSCLC tumors.

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“…66 However, many have exhibited issues with toxicity or resistance due to compensatory mechanisms and feedback loops with closely related signaling pathways, and co-targeted inhibition approaches have been gaining popularity in preclinical studies. [67][68][69][70] Thus, PIM and PI3K co-targeting may be a viable approach owing to the overlap between those pathways, the proven PIMinduced resistance to PI3K inhibition 35 and the reported successful synergism that results when both are used. 71 Synergy between inhibitors could allow the use of lower therapeutic doses to achieve the same clinical effect, thus potentially reducing treatment toxicity and improving patient quality of life.…”

Section: Pim Inhibition Within the Prostate Cancer Clinical Pathwaymentioning

confidence: 99%

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

Luszczak

Kumar

Sathyadevan

et al. 2020

Sig Transduct Target Ther

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PIM kinases have been shown to play a role in prostate cancer development and progression, as well as in some of the hallmarks of cancer, especially proliferation and apoptosis. Their upregulation in prostate cancer has been correlated with decreased patient overall survival and therapy resistance. Initial efforts to inhibit PIM with monotherapies have been hampered by compensatory upregulation of other pathways and drug toxicity, and as such, it has been suggested that co-targeting PIM with other treatment approaches may permit lower doses and be a more viable option in the clinic. Here, we present the rationale and basis for cotargeting PIM with inhibitors of PI3K/mTOR/AKT, JAK/STAT, MYC, stemness, and RNA Polymerase I transcription, along with other therapies, including androgen deprivation, radiotherapy, chemotherapy, and immunotherapy. Such combined approaches could potentially be used as neoadjuvant therapies, limiting the development of resistance to treatments or sensitizing cells to other therapeutics. To determine which drugs should be combined with PIM inhibitors for each patient, it will be key to develop companion diagnostics that predict response to each co-targeted option, hopefully providing a personalized medicine pathway for subsets of prostate cancer patients in the future.

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Strategic targeting of the PI3K–NFκB axis in cisplatin-resistant NSCLC

Cited by 25 publications

References 31 publications

Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells to cisplatin through inhibiting NFκB signaling pathway

Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells to cisplatin through inhibiting NFκB signaling pathway

IL-6 signaling contributes to cisplatin resistance in non-small cell lung cancer via the up-regulation of anti-apoptotic and dna repair associated molecules

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

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Strategic targeting of the PI3K–NFκB axis in cisplatin-resistant NSCLC

Cited by 25 publications

References 31 publications

Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells&nbsp;to cisplatin through inhibiting NF&kappa;B signaling pathway

Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells&nbsp;to cisplatin through inhibiting NF&kappa;B signaling pathway

IL-6 signaling contributes to cisplatin resistance in non-small cell lung cancer via the up-regulation of anti-apoptotic and dna repair associated molecules

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

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Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells to cisplatin through inhibiting NFκB signaling pathway

Combination chemotherapy with Zyflamend reduced the acquired resistance of bladder cancer cells to cisplatin through inhibiting NFκB signaling pathway