Dataset Information

Activated ROCK/Akt/eNOS and ET-1/ERK pathways in 5-fluorouracil-induced cardiotoxicity: modulation by simvastatin.

ABSTRACT: 5-Fluorouracil (5-FU) is used in the treatment of different solid tumors; however, its use is associated with rare, but serious cardiotoxicity. Nevertheless, the involvement of ROCK/NF-?B, Akt/eNOS and ET-1/ERK1/2 trajectories in the cardiotoxic effect and in the potential cardioprotective upshot of simvastatin has been elusive. Male Wistar rats were allocated into 5-FU (50 mg/kg/week; i.p, 6 weeks), simvastatin (15 mg/kg/day; p.o, 8 weeks) treated groups and simvastatin?+?5-FU, besides the normal control group. 5-FU-induced cardiotoxicity boosted the serum level of N-terminal pro-brain (B-type) natriuretic peptide (NT-proBNP), aortic contents of endothelin (ET)-1 and thromboxane (TX) A2, as well as cardiac contents of NADPH oxidases (Nox), cyclooxygenase (COX)-2, malondialdehyde (MDA), phosphorylated Akt (p-Akt), phosphorylated extracellular signal-regulated kinase (p-ERK)1/2 and the protein expressions of rho-kinase (ROCK) and caspase-3. On the other hand, it suppressed cardiac reduced glutathione (GSH) and phosphorylated endothelial nitric oxide synthase (p-eNOS). Contrariwise, co-administration with simvastatin overcame these disturbed events and modulated the ROCK/NF-?B, Akt/eNOS and ET-1/ERK1/2 signaling pathways. This study highlights other mechanisms than coronary artery spasm in the 5-FU cardiotoxicity and reveals that NT-proBNP is a potential early marker in this case. Moreover, the cross-talk between ROCK/ NF-?B, ROS/COX-2/TXA2, Akt/eNOS and ET-1/ERK1/2 pathways contributes via different means to upsetting the vasoconstriction/vasodilatation equilibrium as well as endothelial cell function and finally leads to cardiomyocyte stress and death-the modulation of these trajectories offers simvastatin its potential cardio-protection against 5-FU.

SUBMITTER: Muhammad RN

PROVIDER: S-EPMC7477553 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Activated ROCK/Akt/eNOS and ET-1/ERK pathways in 5-fluorouracil-induced cardiotoxicity: modulation by simvastatin.

Muhammad Radwa Nasser RN Sallam Nada N El-Abhar Hanan Salah HS

Scientific reports 20200907 1

5-Fluorouracil (5-FU) is used in the treatment of different solid tumors; however, its use is associated with rare, but serious cardiotoxicity. Nevertheless, the involvement of ROCK/NF-κB, Akt/eNOS and ET-1/ERK1/2 trajectories in the cardiotoxic effect and in the potential cardioprotective upshot of simvastatin has been elusive. Male Wistar rats were allocated into 5-FU (50 mg/kg/week; i.p, 6 weeks), simvastatin (15 mg/kg/day; p.o, 8 weeks) treated groups and simvastatin + 5-FU, besides the norm ...[more]

PMID: 32895407

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Project description:Sanguisorba officinalis L., a traditional Chinese medicine (TCM) called DiYu (DY) in China, has a strong tradition of utilization as a scorching, blood-cooling, and hemostatic medication, and was used for cancer prevention and treatment due to its potential immune-enhancing and hematological toxicity-reducing effects. Previous studies have reported significant effects of DY on cancers including colorectal cancer (CRC), which is one of the most common malignancies worldwide. The first-line cure 5-fluorouracil (5-FU) plays decisive commerce in the sedative of CRC as a clinically available chemotherapeutic agent. One of the primary causes of cancer treatment failure is the acquisition of chemotherapy drug resistance. In order to successfully combat the emergence of chemoresistance, it is essential to identify herbs or traditional Chinese medicine that have adjuvant therapeutic effects on CRC. Therefore, this study aimed to determine whether DY could improve the sensitivity, conquer the chemoresistance of 5-FU-resistant CRC cells, and investigate its intrinsic mechanism.Materials and methodsMTT, Hoechst 33258 staining, and flow cytometry assays were used to determine the anticancer activity of DY alone or in combination with 5-FU against 5-FU-resistant CRC cells (RKO-R and HCT15-R) and wound healing assays were conducted to detect cell migration. Transcriptomic techniques were carried out to explore the effect and mechanism of DY on drug-resistant CRC cells. Western Blot and RT q-PCR assays were performed to validate the mechanism by which DY overcomes drug-resistant CRC cells.ResultsThese results indicated that DY alone or in combination with 5-FU significantly inhibited the proliferation and the migration of resistant CRC cells, and potentiated the susceptibility of 5-FU to drug-resistant CRC cells. GO and KEGG enrichment analysis showed that the mechanisms of drug resistance in CRC cells and DY against drug-resistant CRC cells highly overlapped, involved in the modulation of biological processes such as cell migration, positive regulation of protein binding and cytoskeleton, and MAPK (Ras-ERK-MEK), PI3K/Akt, and other signaling pathways. Moreover, DY can mediate the expression of p-R-Ras, p-ERK1/2, p-MEK1/2, p-PI3K, p-AKT, HIF-1A and VEGFA proteins. In addition, DY significantly suppressed the expression of AKT3, NEDD9, BMI-1, and CXCL1 genes in resistant CRC cells.ConclusionIn conclusion, DY could inhibit the proliferation and migration of 5-FU-resistant cells and strengthen the sensitivity of 5-FU to CRC-resistant cells. Furthermore, DY may prevail over chemoresistance through the Ras/MEK/ERK and PI3K/Akt pathways. These findings imply that DY may be a potential drug for clinical treatment or adjuvant treatment of drug-resistant CRC.

Dataset Information

Activated ROCK/Akt/eNOS and ET-1/ERK pathways in 5-fluorouracil-induced cardiotoxicity: modulation by simvastatin.

Publications

Activated ROCK/Akt/eNOS and ET-1/ERK pathways in 5-fluorouracil-induced cardiotoxicity: modulation by simvastatin.

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