PMID- 29620191
OWN - NLM
STAT- MEDLINE
DCOM- 20181009
LR  - 20181009
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Linking)
VI  - 52
IP  - 6
DP  - 2018 Jun
TI  - Arsenic disulfide‑induced apoptosis and its potential mechanism in two‑ and 
      three‑dimensionally cultured human breast cancer MCF‑7 cells.
PG  - 1959-1971
LID - 10.3892/ijo.2018.4357 [doi]
AB  - In China, arsenic disulfide (As2S2) has been used for the treatment of 
      hematological malignancies. The present study aimed to evaluate the effects of 
      As2S2 on the human breast cancer MCF‑7 cell line cultured in both 
      two‑dimensional (2D) monolayers and three‑dimensional (3D) spheroids to explore 
      its therapeutic potential in breast cancer treatment. Cellular viability and the 
      induction of apoptosis were examined with a cell counting kit‑8 (CCK‑8) assay and 
      flow cytometric analysis, respectively. Alterations in the expression levels of 
      apoptosis‑associated proteins, including Bcl‑2‑associated X protein (Bax), B‑cell 
      lymphoma 2 (Bcl‑2), p53, and caspase‑7, as well as the cell survival‑associated 
      proteins, phosphatidylinositol 3‑kinase (PI3K), Akt, and mammalian target of 
      rapamycin (mTOR), were assessed by western blotting. Although a dose‑dependent 
      reduction in cell viability, which occurred in association with the induction of 
      apoptosis triggered by the addition of 2‑24 microM As2S2, was observed in both 2D‑ 
      and 3D‑culture systems, 3D spheroids were less sensitive to the cytotoxic effect 
      of As2S2 compared with the 2D cultured cells. A significant increase in the 
      expression levels of Bax, p53, and caspase‑7 was observed in treated 2D‑cultured 
      cells, whereas a similar increase in the expression levels of Bax was only 
      confirmed in treated 3D spheroids, although there was a trend towards the 
      increased expression of p53 and caspase‑7 in the 3D spheroids. These results 
      suggested that these molecules are closely associated with As2S2‑mediated 
      cytotoxicity in the two culture systems, and further suggested that the 
      difference in the sensitivity to As2S2 between 2D monolayers and 3D spheroids may 
      be attributed to the differential alterations in the expression levels of 
      proteins associated with cell mortality. Significant downregulation of the 
      expression levels of Bcl‑2, PI3K, Akt and mTOR was observed in the two culture 
      systems. Taken together, the results of the present study demonstrated that As2S2 
      inhibits cell viability and induces apoptosis in both 2D‑ and 3D‑ cultured MCF‑7 
      cells, which may be associated with activation of the pro‑apoptotic pathway and 
      the inhibition of pro‑survival signaling. These results have provided novel 
      insights into clinical applications of As2S2 in the treatment of patients with 
      breast cancer.
FAU - Zhao, Yuxue
AU  - Zhao Y
AD  - Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of 
      Pharmacy and Life Sciences, Hachioji, Tokyo 192‑0392, Japan.
FAU - Onda, Kenji
AU  - Onda K
AD  - Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of 
      Pharmacy and Life Sciences, Hachioji, Tokyo 192‑0392, Japan.
FAU - Yuan, Bo
AU  - Yuan B
AD  - Department of Applied Biochemistry, School of Pharmacy, Tokyo University of 
      Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
FAU - Tanaka, Sachiko
AU  - Tanaka S
AD  - Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of 
      Pharmacy and Life Sciences, Hachioji, Tokyo 192‑0392, Japan.
FAU - Kiyomi, Anna
AU  - Kiyomi A
AD  - Department of Drug Safety and Risk Management, School of Pharmacy, Tokyo 
      University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
FAU - Sugiyama, Kentaro
AU  - Sugiyama K
AD  - Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of 
      Pharmacy and Life Sciences, Hachioji, Tokyo 192‑0392, Japan.
FAU - Sugiura, Munetoshi
AU  - Sugiura M
AD  - Department of Drug Safety and Risk Management, School of Pharmacy, Tokyo 
      University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
FAU - Takagi, Norio
AU  - Takagi N
AD  - Department of Applied Biochemistry, School of Pharmacy, Tokyo University of 
      Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan.
FAU - Hirano, Toshihiko
AU  - Hirano T
AD  - Department of Clinical Pharmacology, School of Pharmacy, Tokyo University of 
      Pharmacy and Life Sciences, Hachioji, Tokyo 192‑0392, Japan.
LA  - eng
PT  - Journal Article
DEP - 20180404
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Arsenicals)
RN  - 0 (Sulfides)
RN  - 56320-22-0 (arsenic disulfide)
SB  - IM
MH  - Apoptosis Regulatory Proteins/*metabolism
MH  - Arsenicals/*pharmacology
MH  - Breast Neoplasms/drug therapy/*metabolism
MH  - Cell Culture Techniques/*methods
MH  - Cell Cycle/drug effects
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - MCF-7 Cells
MH  - Signal Transduction/drug effects
MH  - Spheroids, Cellular/cytology/*drug effects/metabolism
MH  - Sulfides/*pharmacology
EDAT- 2018/04/06 06:00
MHDA- 2018/10/10 06:00
CRDT- 2018/04/06 06:00
PHST- 2017/09/13 00:00 [received]
PHST- 2018/02/27 00:00 [accepted]
PHST- 2018/04/06 06:00 [pubmed]
PHST- 2018/10/10 06:00 [medline]
PHST- 2018/04/06 06:00 [entrez]
AID - 10.3892/ijo.2018.4357 [doi]
PST - ppublish
SO  - Int J Oncol. 2018 Jun;52(6):1959-1971. doi: 10.3892/ijo.2018.4357. Epub 2018 Apr 
      4.