Doxorubicin Is Key for the Cardiotoxicity of FAC (5-Fluorouracil + Adriamycin + Cyclophosphamide) Combination in Differentiated H9c2 Cells

Pereira-Oliveira, Maria; Reis-Mendes, Ana; Carvalho, Félix; Remião, Fernando; Bastos, Maria de Lourdes; Costa, Vera Marisa

doi:10.3390/biom9010021

Cited by 13 publications

(6 citation statements)

References 51 publications

(87 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of the three drugs, Anthracycline is the drug that most often causes cardiotoxicity. Anthracycline (DOX) was the most cytotoxic drug, followed by 5-FU and lastly CYA in both cytotoxicity assays; even in the presence of higher concentrations of 5-FU and CYA (50 µM 5-FU + 1 µM DOX + 50 µM CYA), 1 µM DOX was still a determinant for the cardiotoxicity observed in the cytotoxicity assays, phase contrast morphological evaluation, and mitochondrial potential depolarization evaluation [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

Cardiotoxicity by Anthracycline Regimen Chemotherapy Prolonged T Peak to T End Interval

et al. 2020

View full text Add to dashboard Cite

Background Myocardial necrosis may occur due to anthracycline (doxorubicin/adriamycin) chemotherapy usage. Furthermore, myocardial necrosis can affect the heterogeneity of heart conduction system and lead to repolarization abnormalities. The aim of this study was to investigate the effect of cardiotoxicity caused by anthracycline to repolarization abnormalities measured by T peak to T end (TpTe) interval. Methods This was a single center prospective cohort study with linear regression from October 2018 to May 2019. The subjects of the study were breast cancer patients after completing administration of chemotherapy with fluorouracil, adriamycin and cyclophosphamide (FAC) regimen (containing anthracycline) for 6 months. Myocardial necrosis was assessed by high sensitive (hs)-troponin I, and the heterogeneity of repolarization was measured by TpTe interval. Results This study involved 25 breast cancer patients after chemotherapy in the 6-month FAC regimen. The mean age is 46 ± 7 years, and the cumulative dose of anthracycline is 591 ± 52 mg/m 2 . The mean level of hs-troponin I is 90.5 ± 44.7 ng/L and the TpTe interval is 108.2 ± 10 ms. The results of linear regression analysis showed a positive correlation between hs-troponin I and TpTe interval (r: 0.421, P: 0.036) after controlling for one confounding variable (cumulative dose of anthracycline). Conclusions Cardiotoxicity caused by accumulative dose of anthracycline may lead to myocardial necrosis which was shown by elevated hs-troponin I levels. This process may lead to heterogeneity conduction system that affect the repolarization phase of cardiac cycle which was shown by increased TpTe interval.

show abstract

Section: Discussionmentioning

confidence: 99%

Cardiotoxicity by Anthracycline Regimen Chemotherapy Prolonged T Peak to T End Interval

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The anticancer drug DOX is a known mitochondrial toxicant [86] and it caused depolarization of the mitochondrial membrane, determinant for FAC mitochondrial toxicity [55]. Herein, we evaluated the mitochondrial membrane potential of H9c2 cells after exposure to the FAC metabolites, tested at clinically relevant concentrations.…”

Section: Discussionmentioning

confidence: 99%

“…For the evaluation of mitochondrial membrane potential, a lipophilic cationic dye, JC-1 was used, as previously described in H9c2 differentiated cells [55]. The JC-1 dye selectively enters into mitochondria and spontaneously forms J-aggregates with intense red fluorescence in the polarized mitochondria.…”

Section: Methodsmentioning

confidence: 99%

“…Whether the metabolism of 5-FU, DOX or CYA contributes to the FAC-induced cytotoxicity has not yet been properly investigated, and to the best of our knowledge, no studies were done to assess the contribution of the main metabolites of DOX, 5-FU or CYA to their cardiotoxicity. Our previous study in H9c2 cells, using clinically relevant concentrations of 5-FU, DOX, and CYA and their combination, demonstrated that DOX was the most toxic drug and key to the toxicity of the combination regimen FAC, while no relevant synergistic or additive effects were observed in the combination settings performed [55]. Nevertheless, in that study the possible contribution of the metabolites towards the observed cardiotoxicity of FAC in clinical settings was not tested.…”

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

The Main Metabolites of Fluorouracil + Adriamycin + Cyclophosphamide (FAC) Are Not Major Contributors to FAC Toxicity in H9c2 Cardiac Differentiated Cells

et al. 2019

Self Cite

View full text Add to dashboard Cite

In the clinical practice, the combination of 5-fluorouracil (5-FU) + Adriamycin (also known as doxorubicin, DOX) + cyclophosphamide (CYA) (known as FAC) is used to treat breast cancer. The FAC therapy, however, carries some serious risks, namely potential cardiotoxic effects, although the mechanisms are still unclear. In the present study, the role of the main metabolites regarding FAC-induced cardiotoxicity was assessed at clinical relevant concentrations. Seven-day differentiated H9c2 cells were exposed for 48 h to the main metabolites of FAC, namely the metabolite of 5-FU, α-fluoro-β-alanine (FBAL, 50 or 100 μM), of DOX, doxorubicinol (DOXOL, 0.2 or 1 μM), and of CYA, acrolein (ACRO, 1 or 10 μM), as well as to their combination. The parent drugs (5-FU 50 μM, DOX 1 μM, and CYA 50 μM) were also tested isolated or in combination with the metabolites. Putative cytotoxicity was evaluated through phase contrast microscopy, Hoechst staining, membrane mitochondrial potential, and by two cytotoxicity assays: the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and the neutral red (NR) lysosomal incorporation. The metabolite DOXOL was more toxic than FBAL and ACRO in the MTT and NR assays. When in combination, neither FBAL nor ACRO increased DOXOL-induced cytotoxicity. No nuclear condensation was observed for any of the tested combinations; however, a significant mitochondrial potential depolarization after FBAL 100 μM + DOXOL 1 μM + ACRO 10 μM or FBAL 100 μM + DOXOL 1 μM exposure was seen at 48 h. When tested alone DOX 1 μM was more cytotoxic than all the parent drugs and metabolites in both the cytotoxicity assays performed. These results demonstrated that DOXOL was the most toxic of all the metabolites tested; nonetheless, the metabolites do not seem to be the major contributors to FAC-induced cardiotoxicity in this cardiac model.

show abstract

“…LMICs are particularly vulnerable to the effects of breast cancer due to the lack of early detection resulting in later stage cancers being diagnosed, which require more aggressive chemotherapy for which there are insufficient adequate treatment options [ 46 ]. Paclitaxel (PTX), cyclophosphamide (CYA), methotrexate, 5-fluorouracil (5-FU), and doxorubicin/Adriamycin (DOX) are commonly used chemotherapy drugs to manage breast cancer [ 47 , 48 ]. However, treatment failure is commonly observed in patients who tend to develop resistance to these drugs, which is attributed to miRNA modifications and aberrant alternative splicing.…”

Section: Mirna and Alternative Splicing-induced Drug Resistancementioning

confidence: 99%

MicroRNA and Alternative mRNA Splicing Events in Cancer Drug Response/Resistance: Potent Therapeutic Targets

et al. 2021

View full text Add to dashboard Cite

Cancer is a multifaceted disease that involves several molecular mechanisms including changes in gene expression. Two important processes altered in cancer that lead to changes in gene expression include altered microRNA (miRNA) expression and aberrant splicing events. MiRNAs are short non-coding RNAs that play a central role in regulating RNA silencing and gene expression. Alternative splicing increases the diversity of the proteome by producing several different spliced mRNAs from a single gene for translation. MiRNA expression and alternative splicing events are rigorously regulated processes. Dysregulation of miRNA and splicing events promote carcinogenesis and drug resistance in cancers including breast, cervical, prostate, colorectal, ovarian and leukemia. Alternative splicing may change the target mRNA 3′UTR binding site. This alteration can affect the produced protein and may ultimately affect the drug affinity of target proteins, eventually leading to drug resistance. Drug resistance can be caused by intrinsic and extrinsic factors. The interplay between miRNA and alternative splicing is largely due to splicing resulting in altered 3′UTR targeted binding of miRNAs. This can result in the altered targeting of these isoforms and altered drug targets and drug resistance. Furthermore, the increasing prevalence of cancer drug resistance poses a substantial challenge in the management of the disease. Henceforth, molecular alterations have become highly attractive drug targets to reverse the aberrant effects of miRNAs and splicing events that promote malignancy and drug resistance. While the miRNA–mRNA splicing interplay in cancer drug resistance remains largely to be elucidated, this review focuses on miRNA and alternative mRNA splicing (AS) events in breast, cervical, prostate, colorectal and ovarian cancer, as well as leukemia, and the role these events play in drug resistance. MiRNA induced cancer drug resistance; alternative mRNA splicing (AS) in cancer drug resistance; the interplay between AS and miRNA in chemoresistance will be discussed. Despite this great potential, the interplay between aberrant splicing events and miRNA is understudied but holds great potential in deciphering miRNA-mediated drug resistance.

show abstract

Doxorubicin Is Key for the Cardiotoxicity of FAC (5-Fluorouracil + Adriamycin + Cyclophosphamide) Combination in Differentiated H9c2 Cells

Cited by 13 publications

References 51 publications

Cardiotoxicity by Anthracycline Regimen Chemotherapy Prolonged T Peak to T End Interval

Cardiotoxicity by Anthracycline Regimen Chemotherapy Prolonged T Peak to T End Interval

The Main Metabolites of Fluorouracil + Adriamycin + Cyclophosphamide (FAC) Are Not Major Contributors to FAC Toxicity in H9c2 Cardiac Differentiated Cells

MicroRNA and Alternative mRNA Splicing Events in Cancer Drug Response/Resistance: Potent Therapeutic Targets

Contact Info

Product

Resources

About