PMID- 33162811
OWN - NLM
STAT- MEDLINE
DCOM- 20210802
LR  - 20211204
IS  - 1449-1907 (Electronic)
IS  - 1449-1907 (Linking)
VI  - 17
IP  - 17
DP  - 2020
TI  - Mitochondrial dysfunction contributes to Rapamycin-induced apoptosis of Human 
      Glioblastoma Cells - A synergistic effect with Temozolomide.
PG  - 2831-2843
LID - 10.7150/ijms.40159 [doi]
AB  - Mammalian target of rapamycin (mTOR) is upregulated in a high percentage of 
      glioblastomas. While a well-known mTOR inhibitor, rapamycin, has been shown to 
      reduce glioblastoma survival, the role of mitochondria in achieving this 
      therapeutic effect is less well known. Here, we examined mitochondrial 
      dysfunction mechanisms that occur with the suppression of mTOR signaling. We 
      found that, along with increased apoptosis, and a reduction in transformative 
      potential, rapamycin treatment significantly affected mitochondrial health. 
      Specifically, increased production of reactive oxygen species (ROS), 
      depolarization of the mitochondrial membrane potential (MMP), and altered 
      mitochondrial dynamics were observed. Furthermore, we verified the therapeutic 
      potential of rapamycin-induced mitochondrial dysfunction through co-treatment 
      with temzolomide (TMZ), the current standard of care for glioblastoma. Together 
      these results demonstrate that the mitochondria remain a promising target for 
      therapeutic intervention against human glioblastoma and that TMZ and rapamycin 
      have a synergistic effect in suppressing glioblastoma viability, enhancing ROS 
      production, and depolarizing MMP.
CI  - (c) The author(s).
FAU - Zimmerman, Mary A
AU  - Zimmerman MA
AD  - Department of Pharmaceutical Sciences, Biomanufacturing Research Institute 
      Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 
      Fayetteville St, Durham, NC, 27707, USA.
AD  - Department of Biology, University of Wisconsin-La Crosse, 1725 State St, La 
      Crosse, WI, 54601, USA.
FAU - Wilkison, Samantha
AU  - Wilkison S
AD  - Department of Pharmaceutical Sciences, Biomanufacturing Research Institute 
      Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 
      Fayetteville St, Durham, NC, 27707, USA.
AD  - Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, 
      27708, USA.
FAU - Qi, Qi
AU  - Qi Q
AD  - Department of Pharmaceutical Sciences, Biomanufacturing Research Institute 
      Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 
      Fayetteville St, Durham, NC, 27707, USA.
AD  - Department of Neurology, Neuroscience Center, General Hospital of Ningxia Medical 
      University, and Key Laboratory of Craniocerebral Diseases of Ningxia Hui 
      Autonomous Region, Yinchuan 750004, China.
FAU - Chen, Guisheng
AU  - Chen G
AD  - Department of Neurology, Neuroscience Center, General Hospital of Ningxia Medical 
      University, and Key Laboratory of Craniocerebral Diseases of Ningxia Hui 
      Autonomous Region, Yinchuan 750004, China.
FAU - Li, P Andy
AU  - Li PA
AD  - Department of Pharmaceutical Sciences, Biomanufacturing Research Institute 
      Biotechnology Enterprise (BRITE), North Carolina Central University, 1801 
      Fayetteville St, Durham, NC, 27707, USA.
LA  - eng
PT  - Journal Article
DEP - 20201016
PL  - Australia
TA  - Int J Med Sci
JT  - International journal of medical sciences
JID - 101213954
RN  - 0 (Reactive Oxygen Species)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
RN  - YF1K15M17Y (Temozolomide)
SB  - IM
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology/therapeutic use
MH  - Apoptosis/drug effects
MH  - Brain Neoplasms/*drug therapy/pathology
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Drug Synergism
MH  - Glioblastoma/*drug therapy/pathology
MH  - Humans
MH  - Membrane Potential, Mitochondrial/drug effects
MH  - Mitochondria/drug effects/pathology
MH  - Mitochondrial Dynamics/drug effects
MH  - Reactive Oxygen Species
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology/therapeutic use
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - Temozolomide/*pharmacology/therapeutic use
PMC - PMC7645350
OTO - NOTNLM
OT  - Rapamycin
OT  - Temozolomide
OT  - glioblastoma
OT  - mTOR signaling
OT  - mitochondrial dynamics
OT  - mitochondrial dysfunction
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2020/11/10 06:00
MHDA- 2021/08/03 06:00
PMCR- 2020/01/01
CRDT- 2020/11/09 05:30
PHST- 2019/09/10 00:00 [received]
PHST- 2020/01/03 00:00 [accepted]
PHST- 2020/11/09 05:30 [entrez]
PHST- 2020/11/10 06:00 [pubmed]
PHST- 2021/08/03 06:00 [medline]
PHST- 2020/01/01 00:00 [pmc-release]
AID - ijmsv17p2831 [pii]
AID - 10.7150/ijms.40159 [doi]
PST - epublish
SO  - Int J Med Sci. 2020 Oct 16;17(17):2831-2843. doi: 10.7150/ijms.40159. eCollection 
      2020.