PMID- 37739323
OWN - NLM
STAT- MEDLINE
DCOM- 20231103
LR  - 20231103
IS  - 1879-3177 (Electronic)
IS  - 0887-2333 (Linking)
VI  - 93
DP  - 2023 Dec
TI  - Everolimus prevents doxorubicin-induced apoptosis in H9c2 cardiomyocytes but not 
      in MCF-7 cancer cells: Cardioprotective roles of autophagy, mitophagy, and AKT.
PG  - 105698
LID - S0887-2333(23)00147-9 [pii]
LID - 10.1016/j.tiv.2023.105698 [doi]
AB  - Cardiotoxicity is a severe side effect of the chemotherapeutic agent doxorubicin 
      (DOX). We recently showed that DOX-induced cardiomyocyte apoptosis and death were 
      attenuated through autophagy pre-induction. Herein, we assessed how the 
      autophagy/mitophagy-inducing antitumor drug everolimus (EVL) affected DOX-induced 
      cytotoxicity in the rat cardiomyocyte cell line H9c2 and human breast cancer cell 
      line MCF-7. Apoptosis was assessed using annexin V assay. Autophagy and mitophagy 
      were assessed using fluorescence assays. Cellular protein levels were determined 
      using western blotting. Pretreatment with EVL (1 nM) before DOX exposure 
      inhibited mammalian target of rapamycin (mTOR) activity, induced autophagy and 
      mitophagy, and activated protein kinase B (AKT) in H9c2 cells. In mitochondria, 
      DOX (1 muM) induced structural damage (decreased membrane potential and release of 
      cytochrome c), increased superoxide levels, decreased apoptosis inhibitor Bcl-2, 
      and increased apoptosis inducer Bax, leading to apoptosis and reduced viability 
      in H9c2 cells. EVL pretreatment suppressed DOX-induced changes. EVL 
      anti-apoptotic effects were inhibited by treatment with MK-2206, a selective AKT 
      inhibitor. Furthermore, EVL suppressed DOX-induced cardiotoxicity through 
      autophagy/mitophagy and AKT activation but did not attenuate DOX-induced 
      apoptosis or reduction in viability in MCF-7 cells. Altogether, EVL can protect 
      cardiomyocytes from DOX-induced apoptosis and toxicity without reducing DOX 
      antitumor effects, allowing safer chemotherapy.
CI  - Copyright (c) 2023. Published by Elsevier Ltd.
FAU - Kanno, Syu-Ichi
AU  - Kanno SI
AD  - Department of Clinical Pharmacotherapeutics, Tohoku Medical and Pharmaceutical 
      University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic 
      address: syu-kan@tohoku-mpu.ac.jp.
FAU - Hara, Akiyoshi
AU  - Hara A
AD  - Department of Clinical Pharmacotherapeutics, Tohoku Medical and Pharmaceutical 
      University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
LA  - eng
PT  - Journal Article
DEP - 20230921
PL  - England
TA  - Toxicol In Vitro
JT  - Toxicology in vitro : an international journal published in association with 
      BIBRA
JID - 8712158
RN  - 80168379AG (Doxorubicin)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Rats
MH  - Apoptosis
MH  - Autophagy
MH  - *Cardiotoxicity/prevention & control
MH  - *Doxorubicin/adverse effects/toxicity
MH  - *Everolimus/pharmacology
MH  - MCF-7 Cells
MH  - Mitophagy
MH  - *Myocytes, Cardiac/drug effects
MH  - *Neoplasms/metabolism
MH  - Oxidative Stress
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction
OTO - NOTNLM
OT  - Apoptosis
OT  - Autophagy
OT  - Cardiomyocyte
OT  - Cytotoxicity
OT  - Doxorubicin
OT  - Everolimus
COIS- Declaration of Competing Interest The authors have no relevant financial or 
      non-financial interests to disclose.
EDAT- 2023/09/23 11:42
MHDA- 2023/10/23 01:18
CRDT- 2023/09/22 19:19
PHST- 2023/05/07 00:00 [received]
PHST- 2023/09/11 00:00 [revised]
PHST- 2023/09/14 00:00 [accepted]
PHST- 2023/10/23 01:18 [medline]
PHST- 2023/09/23 11:42 [pubmed]
PHST- 2023/09/22 19:19 [entrez]
AID - S0887-2333(23)00147-9 [pii]
AID - 10.1016/j.tiv.2023.105698 [doi]
PST - ppublish
SO  - Toxicol In Vitro. 2023 Dec;93:105698. doi: 10.1016/j.tiv.2023.105698. Epub 2023 
      Sep 21.