PMID- 28937626
OWN - NLM
STAT- MEDLINE
DCOM- 20180521
LR  - 20220408
IS  - 1420-3049 (Electronic)
IS  - 1420-3049 (Linking)
VI  - 22
IP  - 10
DP  - 2017 Sep 22
TI  - Aspalathin Reverts Doxorubicin-Induced Cardiotoxicity through Increased Autophagy 
      and Decreased Expression of p53/mTOR/p62 Signaling.
LID - 10.3390/molecules22101589 [doi]
LID - 1589
AB  - Doxorubicin (Dox) is an effective chemotherapeutic agent used in the treatment of 
      various cancers. Its clinical use is often limited due to its potentially fatal 
      cardiotoxic side effect. Increasing evidence indicates that tumour protein p53 
      (p53), adenosine monophosphate-activated protein kinase (AMPK), nucleoporin p62 
      (p62), and the mammalian target of rapamycin (mTOR) are critical mediators of 
      Dox-induced apoptosis, and subsequent dysregulation of autophagy. Aspalathin, a 
      polyphenolic dihydrochalcone C-glucoside has been shown to activate AMPK while 
      decreasing the expression of p53. However, the role that aspalathin could play in 
      the inhibition of Dox-induced cardiotoxicity through increased autophagy flux 
      remained unexplored. H9c2 cardiomyocytes and Caov-3 ovarian cancer cells were 
      cultured in Dulbecco's Modified Eagle's medium and treated with or without Dox 
      for five days. Thereafter, cells exposed to 0.2 microM Dox were co-treated with 
      either 20 microM Dexrazozane (Dexra) or 0.2 microM aspalathin (ASP) daily for 5 days. 
      Results obtained showed that ASP mediates its cytoprotective effect in a 
      p53-dependent manner, by increasing the Bcl-2/Bax ratio and decreasing apoptosis. 
      The latter effect was diminished through ASP-induced activation of 
      autophagy-related genes (Atgs) with an associated decrease in p62 through 
      induction of AMPK and Fox01. Furthermore, we showed that ASP was able to 
      potentiate this effect without decreasing the anti-cancer efficacy of Dox, as 
      could be observed in Caov-3 ovarian cancer cells. Taken together, the data 
      presented in this study provides a credible mechanism by which ASP co-treatment 
      could protect the myocardium from Dox-induced cardiotoxicity.
FAU - Johnson, Rabia
AU  - Johnson R
AUID- ORCID: 0000-0002-6328-0789
AD  - Biomedical Research and Innovation Platform (BRIP), South African Medical 
      Research Council (MRC), Tygerberg 7505, South Africa. rabia.johnson@mrc.ac.za.
AD  - Division of Medical Physiology, Department of Biomedical Sciences, Faculty of 
      Medicine and Health Sciences, Stellenbosch University, Tygerberg 7505, South 
      Africa. rabia.johnson@mrc.ac.za.
FAU - Shabalala, Samukelisiwe
AU  - Shabalala S
AUID- ORCID: 0000-0003-1238-4673
AD  - Biomedical Research and Innovation Platform (BRIP), South African Medical 
      Research Council (MRC), Tygerberg 7505, South Africa. 
      samukelisiwe.shabalala@mrc.ac.za.
AD  - Department of Biochemistry and Microbiology, University of Zululand, Kwadlangezwa 
      3886, South Africa. samukelisiwe.shabalala@mrc.ac.za.
FAU - Louw, Johan
AU  - Louw J
AD  - Biomedical Research and Innovation Platform (BRIP), South African Medical 
      Research Council (MRC), Tygerberg 7505, South Africa. johan.louw@mrc.ac.za.
AD  - Department of Biochemistry and Microbiology, University of Zululand, Kwadlangezwa 
      3886, South Africa. johan.louw@mrc.ac.za.
FAU - Kappo, Abidemi Paul
AU  - Kappo AP
AUID- ORCID: 0000-0003-2521-8957
AD  - Department of Biochemistry and Microbiology, University of Zululand, Kwadlangezwa 
      3886, South Africa. kappoA@unizulu.ac.za.
FAU - Muller, Christo John Frederick
AU  - Muller CJF
AUID- ORCID: 0000-0001-6821-2120
AD  - Biomedical Research and Innovation Platform (BRIP), South African Medical 
      Research Council (MRC), Tygerberg 7505, South Africa. christo.muller@mrc.ac.za.
AD  - Division of Medical Physiology, Department of Biomedical Sciences, Faculty of 
      Medicine and Health Sciences, Stellenbosch University, Tygerberg 7505, South 
      Africa. christo.muller@mrc.ac.za.
AD  - Department of Biochemistry and Microbiology, University of Zululand, Kwadlangezwa 
      3886, South Africa. christo.muller@mrc.ac.za.
LA  - eng
PT  - Journal Article
DEP - 20170922
PL  - Switzerland
TA  - Molecules
JT  - Molecules (Basel, Switzerland)
JID - 100964009
RN  - 0 (Chalcones)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0 (aspalathin)
RN  - 048L81261F (Dexrazoxane)
RN  - 80168379AG (Doxorubicin)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Autophagy/drug effects
MH  - Cardiomyopathies/metabolism
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Chalcones/pharmacology
MH  - Dexrazoxane/pharmacology
MH  - Doxorubicin/chemistry/*pharmacology
MH  - Humans
MH  - Oxidative Stress/drug effects
MH  - Rats
MH  - Signal Transduction/drug effects
MH  - Tumor Suppressor Protein p53/metabolism
PMC - PMC6151817
OTO - NOTNLM
OT  - apoptosis
OT  - aspalathin
OT  - autophagy
OT  - cardiomyopathy
OT  - cardiotoxicity
OT  - doxorubicin
OT  - oxidative stress
COIS- The authors declare no conflict of interest.
EDAT- 2017/09/25 06:00
MHDA- 2018/05/22 06:00
PMCR- 2017/09/22
CRDT- 2017/09/23 06:00
PHST- 2017/08/24 00:00 [received]
PHST- 2017/09/18 00:00 [revised]
PHST- 2017/09/19 00:00 [accepted]
PHST- 2017/09/23 06:00 [entrez]
PHST- 2017/09/25 06:00 [pubmed]
PHST- 2018/05/22 06:00 [medline]
PHST- 2017/09/22 00:00 [pmc-release]
AID - molecules22101589 [pii]
AID - molecules-22-01589 [pii]
AID - 10.3390/molecules22101589 [doi]
PST - epublish
SO  - Molecules. 2017 Sep 22;22(10):1589. doi: 10.3390/molecules22101589.