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TP53 alteration determines the combinational cytotoxic effect of doxorubicin and an antioxidant NAC.

Abstract The anticancer effect of doxorubicin is closely related to the generation of reactive oxygen species. On the contrary, doxorubicin-induced reactive oxygen species induces heart failure, a critical side effect of doxorubicin. Antioxidant supplementation has been proposed to reduce the side effects. However, the use of antioxidants may hamper the anticancer effect of doxorubicin. In this study, doxorubicin-induced reactive oxygen species was shown to differentially affect cancer cells based on their TP53 genetic status; doxorubicin-induced apoptosis was attenuated by an antioxidant, N-acetylcysteine, in TP53 wild cells; however, N-acetylcysteine caused a synergistic increase in the apoptosis rate in TP53-altered cells. N-acetylcysteine prevented phosphorylation of P53 protein that had been induced by doxorubicin. However, N-acetylcysteine increased the cleavage of poly (ADP-ribose) polymerase in the presence of doxorubicin. Synergy score of 26 patient-derived cells were evaluated after the combination treatment of doxorubicin and N-acetylcysteine. The synergy score was significantly higher in TP53-altered group compared with those in TP53 wild group. In conclusion, TP53 genetic alteration is a critical factor that determines the use of antioxidant supplements during doxorubicin treatment.
PMID
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Authors

Mayor MeshTerms

Drug Synergism

Keywords

N-acetylcysteine

TP53

apoptosis

doxorubicin

reactive oxygen species

Journal Title tumour biology : the journal of the international society for oncodevelopmental biology and medicine
Publication Year Start




PMID- 28653879
OWN - NLM
STAT- MEDLINE
DA  - 20170627
DCOM- 20170711
LR  - 20170713
IS  - 1423-0380 (Electronic)
IS  - 1010-4283 (Linking)
VI  - 39
IP  - 6
DP  - 2017 Jun
TI  - TP53 alteration determines the combinational cytotoxic effect of doxorubicin and 
      an antioxidant NAC.
PG  - 1010428317700159
LID - 10.1177/1010428317700159 [doi]
AB  - The anticancer effect of doxorubicin is closely related to the generation of
      reactive oxygen species. On the contrary, doxorubicin-induced reactive oxygen
      species induces heart failure, a critical side effect of doxorubicin. Antioxidant
      supplementation has been proposed to reduce the side effects. However, the use of
      antioxidants may hamper the anticancer effect of doxorubicin. In this study,
      doxorubicin-induced reactive oxygen species was shown to differentially affect
      cancer cells based on their TP53 genetic status; doxorubicin-induced apoptosis
      was attenuated by an antioxidant, N-acetylcysteine, in TP53 wild cells; however, 
      N-acetylcysteine caused a synergistic increase in the apoptosis rate in
      TP53-altered cells. N-acetylcysteine prevented phosphorylation of P53 protein
      that had been induced by doxorubicin. However, N-acetylcysteine increased the
      cleavage of poly (ADP-ribose) polymerase in the presence of doxorubicin. Synergy 
      score of 26 patient-derived cells were evaluated after the combination treatment 
      of doxorubicin and N-acetylcysteine. The synergy score was significantly higher
      in TP53-altered group compared with those in TP53 wild group. In conclusion, TP53
      genetic alteration is a critical factor that determines the use of antioxidant
      supplements during doxorubicin treatment.
FAU - Lee, Yun Sun
AU  - Lee YS
AD  - 1 Department of Orthopaedic Surgery, Samsung Medical Center, Sungkyunkwan
      University School of Medicine, Seoul, Korea.
FAU - Choi, Young Joon
AU  - Choi YJ
AD  - 1 Department of Orthopaedic Surgery, Samsung Medical Center, Sungkyunkwan
      University School of Medicine, Seoul, Korea.
FAU - Lee, JeeYun
AU  - Lee J
AD  - 2 Department of Medicine, Division of Hematology-Oncology, Samsung Medical
      Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
FAU - Shim, Da Mi
AU  - Shim DM
AD  - 1 Department of Orthopaedic Surgery, Samsung Medical Center, Sungkyunkwan
      University School of Medicine, Seoul, Korea.
FAU - Park, Woong-Yang
AU  - Park WY
AD  - 3 Samsung Genome Institute, Samsung Medical Center, Sungkyunkwan University
      School of Medicine, Seoul, South Korea.
FAU - Seo, Sung Wook
AU  - Seo SW
AD  - 1 Department of Orthopaedic Surgery, Samsung Medical Center, Sungkyunkwan
      University School of Medicine, Seoul, Korea.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Tumour Biol
JT  - Tumour biology : the journal of the International Society for Oncodevelopmental
      Biology and Medicine
JID - 8409922
RN  - 0 (Antioxidants)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 80168379AG (Doxorubicin)
RN  - WYQ7N0BPYC (Acetylcysteine)
SB  - IM
MH  - A549 Cells
MH  - Acetylcysteine/*administration & dosage
MH  - Antioxidants/administration & dosage
MH  - Apoptosis/drug effects
MH  - Cell Proliferation/drug effects
MH  - Doxorubicin/administration & dosage/adverse effects
MH  - *Drug Synergism
MH  - Heart Failure/chemically induced/*drug therapy/pathology
MH  - Humans
MH  - MCF-7 Cells
MH  - Neoplasms/*drug therapy/pathology
MH  - Phosphorylation
MH  - Reactive Oxygen Species/metabolism
MH  - Tumor Suppressor Protein p53/*genetics
OTO - NOTNLM
OT  - N-acetylcysteine
OT  - TP53
OT  - apoptosis
OT  - doxorubicin
OT  - reactive oxygen species
EDAT- 2017/06/28 06:00
MHDA- 2017/07/14 06:00
CRDT- 2017/06/28 06:00
AID - 10.1177/1010428317700159 [doi]
PST - ppublish
SO  - Tumour Biol. 2017 Jun;39(6):1010428317700159. doi: 10.1177/1010428317700159.