Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

Lagadec, Patricia; Griessinger, Emmanuel; Nawrot, M P; Fenouille, Nina; Colosetti, P.; Imbert, Véronique; Mari, Mireille; Hofman, Paul; Czerucka, Dorota; Rousseau, Denis; Bérard, Étienne; Dréano, Michel; Peyron, Jean‐François

doi:10.1038/sj.bjc.6604082

Cited by 25 publications

(26 citation statements)

References 37 publications

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“…In patients with colorectal cancer, CPT-11 (irinotecan), a topoisomerase inhibitor, can induce chemoresistance in malignant cells via activation of the NF-κB pathway (36)(37)(38). DNA topoisomerases are molecules that modulate chromosome superstructure and integrity via cutting, shuffling DNA strands, removing DNA supercoils, and disentangling snarled DNA segments (39).…”

Section: Discussionmentioning

confidence: 99%

Anticancer effect of SZC017, a novel derivative of oleanolic acid, on human gastric cancer cells

Gao

Wang

et al. 2015

Oncology Reports

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Abstract. Oleanolic acid (OA) and its several derivatives possess chemopreventive and chemotherapeutic functions against a series of cancer types. Many chemotherapeutic compounds are effective in improving the quality of life and prolonging the survival of patients with gastric cancer, therefore progress in the treatment of gastric cancer, especially the anticancer effects of OA derivatives must be achieved. The inhibitory effect of SZC017, a newly synthesized derivative of OA, on cell viability was determined by MTT assay. Furthermore, flow cytometry, transmission electron microscopy, and western blot analysis revealed that the inhibition of cell viability by OA was mediated by triggering the intrinsic apoptosis of gastric cancer cells, and inducing S phase arrest of SGC7901 cells. Mechanistically, SZC017 was effective against gastric cancer cells via inhibiting Akt/NF-κB signaling and topoisomerase I and IIα proteins. Taken together, our data indicate that SZC017 may be a potential chemotherapeutic agent against gastric cancer cells.

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Section: Discussionmentioning

confidence: 99%

Anticancer effect of SZC017, a novel derivative of oleanolic acid, on human gastric cancer cells

Gao

Wang

et al. 2015

Oncology Reports

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“…Moreover, oleanolic acid also inhibited topoisomerase I and IIα proteins, which are key enzymes involved in tumor cell proliferation, by relaxing DNA supercoiling inside cells [63]. It has been demonstrated that topoisomerase inhibition activates the NF‑κB pathway [79]. The suppression of Top-I and Top-IIα resulted in the inhibition of the NF‑κB pathway via p‑IκBα and p‑p65‑dependent manner [63].…”

Section: Oleanolic Acid As Anticancer Agentmentioning

confidence: 99%

Oleanolic Acid Alters Multiple Cell Signaling Pathways: Implication in Cancer Prevention and Therapy

Žiberna

Šamec

Mocan

et al. 2017

IJMS

116

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Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the multifaceted nature of cancer. Increasingly, it is being realized that deregulation of spatio-temporally controlled intracellular signaling cascades plays a contributory role in the onset and progression of cancer. Therefore, targeting regulators of oncogenic signaling cascades is essential to prevent and treat cancer. A plethora of preclinical and epidemiological evidences showed promising role of phytochemicals against several types of cancer. Oleanolic acid, a common pentacyclic triterpenoid, is mainly found in olive oil, as well as several plant species. It is a potent inhibitor of cellular inflammatory process and a well-known inducer of phase 2 xenobiotic biotransformation enzymes. Main molecular mechanisms underlying anticancer effects of oleanolic acid are mediated by caspases, 5 adenosine monophosphate-activated protein kinase, extracellular signal-regulated kinase 1/2, matrix metalloproteinases, pro-apoptotic Bax and bid, phosphatidylinositide 3-kinase/Akt1/mechanistic target of rapamycin, reactive oxygen species/apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase, nuclear factor-κB, cluster of differentiation 1, CKD4, s6k, signal transducer and activator of transcription 3, as well as aforementioned signaling pathways . In this work, we critically review the scientific literature on the molecular targets of oleanolic acid implicated in the prevention and treatment of several types of cancer. We also discuss chemical aspects, natural sources, bioavailability, and safety of this bioactive phytochemical.

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“…MiR-125, especially miR-125b, has been reported to be regulated by NF-kb depending on the cellular context (27,28). Meanwhile, cytotoxic chemotherapies such as CDDP, ETP, and CPT-11 are well known for activating NF-kb (29)(30)(31). In this context, although we could not demonstrate the significant HER2 upregulation by treatment with ETP, we suppose that chemotherapy exposure first induces NF-kb activation and correspondingly downregulates miR-125a and miR-125b expressions.…”

Section: Discussionmentioning

confidence: 99%

Chemotherapy-Regulated microRNA-125–HER2 Pathway as a Novel Therapeutic Target for Trastuzumab-Mediated Cellular Cytotoxicity in Small Cell Lung Cancer

Yagishita

Fujita

Kitazono³

et al. 2015

Molecular Cancer Therapeutics

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Small cell lung cancer (SCLC) accounts for 15% of all lung cancer cases and is a highly lethal disease. For the last several decades, the standard treatment for SCLC has been deadlocked, and new therapeutic strategies are urgently needed. HER2 is a member of the HER family and has been reported to be overexpressed in 30% of SCLC cases with poor prognosis. However, the clinical relevance of HER2-targeted therapy for SCLC remains unclear. Here, we first identify that cytotoxic drugs induce significant HER2 overexpression through microRNA-125a (miR-125a) and miR-125b downregulation, which in turn act as a novel therapeutic target for trastuzumab-mediated cellular cytotoxicity in SCLC. In this study, we showed that treatment of the HER2-positive SCLC cells, SBC-3 and SBC-5, with cytotoxic drugs induced a significant upregulation of HER2. Cisplatin (CDDP) treatment of SCLC cells resulted in a significant downregulation of miR-125a and miR-125b. We confirmed that miR-125a and miR125b bound to the 3 0 -untranslated regions of HER2 mRNA, and that downregulation of miR-125a and miR-125b resulted in upregulation of HER2 in SCLC cells, suggesting a relationship between cytotoxic drug exposure and miR-125/HER2 dysregulation. Furthermore, using a calcein assay, we demonstrated a significantly enhanced cytotoxic effect of CDDP and trastuzumab that was mediated via antibody-dependent cellular cytotoxicity. Finally, we clearly demonstrated the enhanced antitumor effect of these agents in an orthotopic lung cancer model in vivo. Our results offer a novel therapeutic strategy for HER2-positive SCLCs by using trastuzumab combined with cytotoxic drugs.

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Pharmacological targeting of NF-κB potentiates the effect of the topoisomerase inhibitor CPT-11 on colon cancer cells

Cited by 25 publications

References 37 publications

Anticancer effect of SZC017, a novel derivative of oleanolic acid, on human gastric cancer cells

Anticancer effect of SZC017, a novel derivative of oleanolic acid, on human gastric cancer cells

Oleanolic Acid Alters Multiple Cell Signaling Pathways: Implication in Cancer Prevention and Therapy

Chemotherapy-Regulated microRNA-125–HER2 Pathway as a Novel Therapeutic Target for Trastuzumab-Mediated Cellular Cytotoxicity in Small Cell Lung Cancer

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