PMID- 36829578
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230228
IS  - 2079-7737 (Print)
IS  - 2079-7737 (Electronic)
IS  - 2079-7737 (Linking)
VI  - 12
IP  - 2
DP  - 2023 Feb 14
TI  - Temozolomide, Simvastatin and Acetylshikonin Combination Induces 
      Mitochondrial-Dependent Apoptosis in GBM Cells, Which Is Regulated by Autophagy.
LID - 10.3390/biology12020302 [doi]
LID - 302
AB  - Glioblastoma multiforme (GBM) is one of the deadliest cancers. Temozolomide (TMZ) 
      is the most common chemotherapy used for GBM patients. Recently, combination 
      chemotherapy strategies have had more effective antitumor effects and focus on 
      slowing down the development of chemotherapy resistance. A combination of TMZ and 
      cholesterol-lowering medications (statins) is currently under investigation in in 
      vivo and clinical trials. In our current investigation, we have used a 
      triple-combination therapy of TMZ, Simvastatin (Simva), and acetylshikonin, and 
      investigated its apoptotic mechanism in GBM cell lines (U87 and U251). We used 
      viability, apoptosis, reactive oxygen species, mitochondrial membrane potential 
      (MMP), caspase-3/-7, acridine orange (AO) and immunoblotting autophagy assays. 
      Our results showed that a TMZ/Simva/ASH combination therapy induced significantly 
      more apoptosis compared to TMZ, Simva, ASH, and TMZ/Simva treatments in GBM 
      cells. Apoptosis via TMZ/Simva/ASH treatment induced mitochondrial damage 
      (increase of ROS, decrease of MMP) and caspase-3/7 activation in both GBM cell 
      lines. Compared to all single treatments and the TMZ/Simva treatment, 
      TMZ/Simva/ASH significantly increased positive acidic vacuole organelles. We 
      further confirmed that the increase of AVOs during the TMZ/Simva/ASH treatment 
      was due to the partial inhibition of autophagy flux (accumulation of LC3beta-II and 
      a decrease in p62 degradation) in GBM cells. Our investigation also showed that 
      TMZ/Simva/ASH-induced cell death was depended on autophagy flux, as further 
      inhibition of autophagy flux increased TMZ/Simva/ASH-induced cell death in GBM 
      cells. Finally, our results showed that TMZ/Simva/ASH treatment potentially 
      depends on an increase of Bax expression in GBM cells. Our current investigation 
      might open new avenues for a more effective treatment of GBM, but further 
      investigations are required for a better identification of the mechanisms.
FAU - Hajiahmadi, Sima
AU  - Hajiahmadi S
AD  - Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti 
      University of Medical Sciences, Tehran 1985717443, Iran.
FAU - Lorzadeh, Shahrokh
AU  - Lorzadeh S
AUID- ORCID: 0000-0001-8377-8130
AD  - Department of Human Anatomy and Cell Science, Max Rady College of Medicine, 
      University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
FAU - Iranpour, Rosa
AU  - Iranpour R
AD  - Department of Human Anatomy and Cell Science, Max Rady College of Medicine, 
      University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
FAU - Karima, Saeed
AU  - Karima S
AD  - Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti 
      University of Medical Sciences, Tehran 1985717443, Iran.
FAU - Rajabibazl, Masoumeh
AU  - Rajabibazl M
AD  - Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti 
      University of Medical Sciences, Tehran 1985717443, Iran.
FAU - Shahsavari, Zahra
AU  - Shahsavari Z
AUID- ORCID: 0000-0002-4451-7525
AD  - Department of Clinical Biochemistry, Faculty of Medicine, Shahid Beheshti 
      University of Medical Sciences, Tehran 1985717443, Iran.
FAU - Ghavami, Saeid
AU  - Ghavami S
AUID- ORCID: 0000-0001-5948-508X
AD  - Department of Human Anatomy and Cell Science, Max Rady College of Medicine, 
      University of Manitoba, Winnipeg, MB R3E 0V9, Canada.
AD  - Faculty of Medicine in Zabrze, Academia of Silesia, 41-800 Zabrze, Poland.
AD  - Research Institute of Oncology and Hematology, Cancer Care Manitoba, University 
      of Manitoba, Winnipeg, MB R3T 2N2, Canada.
LA  - eng
GR  - 54304/University of Manitoba/
PT  - Journal Article
DEP - 20230214
PL  - Switzerland
TA  - Biology (Basel)
JT  - Biology
JID - 101587988
PMC - PMC9953749
OTO - NOTNLM
OT  - Bcl2 family proteins
OT  - caspase dependent apoptosis
OT  - intrinsic apoptosis pathway
OT  - natural compounds
OT  - statin
COIS- The authors declare no conflict of interest.
EDAT- 2023/02/26 06:00
MHDA- 2023/02/26 06:01
PMCR- 2023/02/14
CRDT- 2023/02/25 01:04
PHST- 2023/01/12 00:00 [received]
PHST- 2023/02/07 00:00 [revised]
PHST- 2023/02/10 00:00 [accepted]
PHST- 2023/02/25 01:04 [entrez]
PHST- 2023/02/26 06:00 [pubmed]
PHST- 2023/02/26 06:01 [medline]
PHST- 2023/02/14 00:00 [pmc-release]
AID - biology12020302 [pii]
AID - biology-12-00302 [pii]
AID - 10.3390/biology12020302 [doi]
PST - epublish
SO  - Biology (Basel). 2023 Feb 14;12(2):302. doi: 10.3390/biology12020302.