Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis

Vyas, Dinesh; Laput, Gieric; Vyas, Arpita

doi:10.2147/ott.s60114

Cited by 250 publications

(209 citation statements)

References 93 publications

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“…Interestingly, NFkB-IL6 signaling has been implicated in the self-renewal, chemoresistance, and tumorigenesis (14,(44)(45)(46)(47). The involvement of NFkB-IL6 signaling in our ex vivo and in vitro models prompted us to evaluate the role of aspirin in abrogating this pathway to chemosensitize resistant breast tumors.…”

Section: Discussionmentioning

confidence: 99%

Aspirin Suppresses the Acquisition of Chemoresistance in Breast Cancer by Disrupting an NFκB–IL6 Signaling Axis Responsible for the Generation of Cancer Stem Cells

et al. 2016

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Acquired chemoresistance has curtailed cancer survival since the dawn of chemotherapy. Accumulating evidence suggests a major role for cancer stem cells (CSC) in chemoresistance, although their involvement in acquired resistance is still unknown. The use of aspirin has been associated with reduced cancer risk and recurrence, suggesting that the anti-inflammatory drug may exert effects on CSCs. In this study, we investigated the contribution of CSCs to acquired chemoresistance of breast cancer and the avenues for reversing such effects with aspirin. We observed that the residual risk of recurrence was higher in breast cancer patients who had acquired chemoresistance. Treatment of preexisting CSCs with a genotoxic drug combination (5-fluorouracil, doxorubicin, and cyclophosphamide) generated an NFkB-IL6-dependent inflammatory environment that imparted stemness to nonstem cancer cells, induced multidrug resistance, and enhanced the migration potential of CSCs. Treatment with aspirin prior to chemotherapy suppressed the acquisition of chemoresistance by perturbing the nuclear translocation of NFkB in preexisting CSCs. Therefore, disruptions to the NFkB-IL6 feedback loop prevented CSC induction and sensitized preexisting CSCs to chemotherapy. Collectively, our findings suggest that combining aspirin and conventional chemotherapy may offer a new treatment strategy to improve recurrence-free survival of breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

Aspirin Suppresses the Acquisition of Chemoresistance in Breast Cancer by Disrupting an NFκB–IL6 Signaling Axis Responsible for the Generation of Cancer Stem Cells

et al. 2016

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“…Activation of NF-κB and resultant inflammatory response have been noted after tumor or host cell exposure to at least five drugs other than PXL including doxorubicin, 5-fluoracil (5-FU), oxaliplatin, cyclophosphamide (CTX), and cisplatin (36). Similarly to PXL, stimulation of the NF-κB pathway by these drugs led to activation of the MAPK pathway, upregulation of the pro-inflammatory AP-2 transcription factor (37), and overexpression of inflammatory (36), prosurvival (29), and migratory genes (38). The TLR4 dependent inflammatory response induced by various chemodrugs was also implicated in promoting epithelial-mesenchymal transition (36) and selecting tumor cells with the stem-like phenotype (39).…”

Section: Introductionmentioning

confidence: 99%

The Role of TLR4 in Chemotherapy-Driven Metastasis

Ran

2015

Cancer Research

105

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Tumor resistance to cytotoxic drugs is one of the main obstacles to successful cancer therapy. Emerging evidence suggests that chemoresistance is promoted by substances released from dead and damaged cells that activate the host repair program orchestrated by Toll-like receptor-4 (TLR4). TLR4 is often overexpressed in malignant and tumor infiltrating immune cells. In addition to endogenous ligands released by therapy-induced tumor destruction, TLR4 is directly activated by paclitaxel, one of the most commonly used chemotherapeutic drugs against various human cancers. TLR4 activation promotes local and systemic inflammation leading to induction of multiple circuits that create a regenerative environment favoring local recurrence and metastasis. Of particular importance is TLR4-mediated recruitment of endothelial progenitors derived from immature myeloid cells. These cells play a major role in rebuilding tumor-associated lymphatic and blood vessels thereby promoting lymphatic and hematogenous metastasis. The latter is further enhanced by the premetastatic niche generated by mobilization of myeloid provascular cells to distant organs. This review summarizes the recent evidence demonstrating that paclitaxel and other clinically used anticancer drugs actively induce metastasis even while shrinking the primary tumor. Better understanding of the mechanisms underlying TLR4 dependent chemotherapy-driven metastasis might be the key to overcoming challenges of cancer eradication.

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“…ADR has previously been shown to induce inflammation in some cancer line by elevation of some inflammatory markers, e.g., IL-1, TNF-α, and NF-KB. NF-κB is also activated by p53 in inflammation induced by ADR [31].…”

Section: Discussionmentioning

confidence: 99%

Counteraction of Apoptotic and Inflammatory Effects of Adriamycin in the Liver Cell Culture by Clinopitolite

Yapışlar

Taşkın

Ozdas

et al. 2015

Biol Trace Elem Res

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Growing evidence has been reported on adriamycin (ADR) hepatotoxicity in literature. Hepatotoxicity caused by the use of drugs has a serious undesirable effect in the cure of cancer patients that needs to be eliminated. The exact mechanism of ADR on non-cancerous tissue still remains to be a mystery. The zeolite (clinoptilolite) minerals form a complex group of aluminosilicates that often occur as accessory minerals in intermediate and basic rocks. In light of this information, we investigated the possible anti-inflammatory and anti-apoptotic effects of clinoptilolite in ADR that is inducing the toxicity in primary liver cell culture. Primary liver cell culture from rat was used in the study. We had three experiment groups including the following: (1) cells treated only with 50 μM ADR for 24 h, (2) cells treated with the 50 μM ADR for 24 h and then treated with 10(-4) M zeolite for 1 h, and (3) cells were incubated with 50 μM ADR for 24 h and then incubated with 10(-4) M zeolite for 24 h to test its long-term effects. After that, western blotting was performed in order to evaluate protein expression levels of several inflammation markers including IL-1β, tumor necrosis factor (TNF)-α, and nuclear factor kappa B (NF-κB), and immunohistochemistry was carried out to detect apoptosis in liver cell culture. Also, TdT-dUTP Terminal Nick-End Labeling (TUNEL) method was used for detecting apoptosis. We found elevated levels of inflammatory protein and apoptotic markers in ADR-administered cells (p < 0.05). Inflammatory and apoptotic markers decreased significantly after treated with zeolite (p < 0.05). The present study was pointed out that ADR causes hepatotoxicity via apoptosis and/or inflammation processes resulting from initiator NF-κB and TNF which causes proinflammatory mediators such as IL-1β. Elevation of inflammation might give rise to trigger apoptosis. Clinoptilolite counteracted the apoptosis and inflammation induced by ADR arising from the decrease in NF-κB, TNF-α, and IL-1β protein levels.

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Chemotherapy-enhanced inflammation may lead to the failure of therapy and metastasis

Cited by 250 publications

References 93 publications

Aspirin Suppresses the Acquisition of Chemoresistance in Breast Cancer by Disrupting an NFκB–IL6 Signaling Axis Responsible for the Generation of Cancer Stem Cells

Aspirin Suppresses the Acquisition of Chemoresistance in Breast Cancer by Disrupting an NFκB–IL6 Signaling Axis Responsible for the Generation of Cancer Stem Cells

The Role of TLR4 in Chemotherapy-Driven Metastasis

Counteraction of Apoptotic and Inflammatory Effects of Adriamycin in the Liver Cell Culture by Clinopitolite

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