PMID- 33754064
OWN - NLM
STAT- MEDLINE
DCOM- 20210729
LR  - 20211204
IS  - 1838-7640 (Electronic)
IS  - 1838-7640 (Linking)
VI  - 11
IP  - 9
DP  - 2021
TI  - Compensatory combination of mTOR and TrxR inhibitors to cause oxidative stress 
      and regression of tumors.
PG  - 4335-4350
LID - 10.7150/thno.52077 [doi]
AB  - Background: Cancer is a leading cause of death worldwide. Extensive research over 
      decades has led to the development of therapies that inhibit oncogenic signaling 
      pathways. The mammalian target of rapamycin (mTOR) signaling pathway plays an 
      important role in the development of many cancers. Several mTOR inhibitors are 
      approved for the treatment of cancers. However, the anticancer efficacies of mTOR 
      inhibitor monotherapy are still limited. Methods: Western blot was used to detect 
      the expression of indicated molecules. Thioredoxin reductase (TrxR) activity in 
      cells was determined by the endpoint insulin reduction assay. Immunofluorescence 
      staining was used to analyze precise location and expression of target proteins. 
      Nude mice were used for xenograft tumor models. Results: We identified a 
      synergistic lethal interaction of mTOR and TrxR inhibitors and elucidated the 
      underlying molecular mechanisms of this synergism. We demonstrated that mTOR and 
      TrxR inhibitors cooperated to induce cell death by triggering oxidative stress, 
      which led to activation of autophagy, endoplasmic reticulum (ER) stress and c-Jun 
      N-terminal Kinase (JNK) signaling pathway in cancer cells. Remarkably, we found 
      that auranofin (AF) combined with everolimus significantly suppressed tumor 
      growth in HCT116 and SGC-7901 xenograft models with no significant signs of 
      toxicity. Conclusion: Our findings identify a promising therapeutic combination 
      for cancer and has important implications for developing mTOR inhibitor-based 
      combination treatments.
CI  - (c) The author(s).
FAU - Xia, Yiqun
AU  - Xia Y
AD  - The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical 
      University, Wenzhou 325035, China.
FAU - Chen, Jundixia
AU  - Chen J
AD  - Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, 
      Wenzhou Medical University, Wenzhou 325035, China.
FAU - Yu, Yun
AU  - Yu Y
AD  - Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, 
      Wenzhou Medical University, Wenzhou 325035, China.
FAU - Wu, Fengjiao
AU  - Wu F
AD  - Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, 
      Wenzhou Medical University, Wenzhou 325035, China.
FAU - Shen, Xin
AU  - Shen X
AD  - Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, 
      Wenzhou Medical University, Wenzhou 325035, China.
FAU - Qiu, Chenyu
AU  - Qiu C
AD  - Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, 
      Wenzhou Medical University, Wenzhou 325035, China.
FAU - Zhang, Tingting
AU  - Zhang T
AD  - Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, 
      Wenzhou Medical University, Wenzhou 325035, China.
FAU - Hong, Lin
AU  - Hong L
AD  - Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, 
      Wenzhou Medical University, Wenzhou 325035, China.
FAU - Zheng, Peisen
AU  - Zheng P
AD  - Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, 
      Wenzhou Medical University, Wenzhou 325035, China.
FAU - Shao, Rongrong
AU  - Shao R
AD  - Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, 
      Wenzhou Medical University, Wenzhou 325035, China.
FAU - Xu, Chenxin
AU  - Xu C
AD  - Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, 
      Wenzhou Medical University, Wenzhou 325035, China.
FAU - Wu, Fang
AU  - Wu F
AD  - The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical 
      University, Wenzhou 325035, China.
FAU - Chen, Wei
AU  - Chen W
AD  - The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical 
      University, Wenzhou 325035, China.
FAU - Xie, Congying
AU  - Xie C
AD  - The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical 
      University, Wenzhou 325035, China.
FAU - Cui, Ri
AU  - Cui R
AD  - The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical 
      University, Wenzhou 325035, China.
AD  - Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, 
      Wenzhou Medical University, Wenzhou 325035, China.
AD  - Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou 
      University, Wenzhou 325035, China.
AD  - Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of 
      Biomedical, Wenzhou 325035, China.
FAU - Zou, Peng
AU  - Zou P
AD  - The First Affiliated Hospital of Wenzhou Medical University, Wenzhou Medical 
      University, Wenzhou 325035, China.
AD  - Cancer and Anticancer Drug Research Center, School of Pharmaceutical Sciences, 
      Wenzhou Medical University, Wenzhou 325035, China.
AD  - Wenzhou University-Wenzhou Medical University Collaborative Innovation Center of 
      Biomedical, Wenzhou 325035, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210225
PL  - Australia
TA  - Theranostics
JT  - Theranostics
JID - 101552395
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 1.8.1.9 (Thioredoxin-Disulfide Reductase)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Autophagy/drug effects
MH  - Cell Death/drug effects
MH  - Cell Line, Tumor
MH  - Endoplasmic Reticulum Stress/drug effects
MH  - HCT116 Cells
MH  - Humans
MH  - MAP Kinase Signaling System/drug effects
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Oxidative Stress/*drug effects
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Thioredoxin-Disulfide Reductase/*antagonists & inhibitors
PMC - PMC7977446
OTO - NOTNLM
OT  - autophagy
OT  - c-Jun N-terminal Kinase
OT  - mTOR
OT  - oxidative stress
OT  - thioredoxin reductase
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2021/03/24 06:00
MHDA- 2021/07/30 06:00
PMCR- 2021/01/01
CRDT- 2021/03/23 06:56
PHST- 2020/08/17 00:00 [received]
PHST- 2021/01/31 00:00 [accepted]
PHST- 2021/03/23 06:56 [entrez]
PHST- 2021/03/24 06:00 [pubmed]
PHST- 2021/07/30 06:00 [medline]
PHST- 2021/01/01 00:00 [pmc-release]
AID - thnov11p4335 [pii]
AID - 10.7150/thno.52077 [doi]
PST - epublish
SO  - Theranostics. 2021 Feb 25;11(9):4335-4350. doi: 10.7150/thno.52077. eCollection 
      2021.