PMID- 38203186
OWN - NLM
STAT- MEDLINE
DCOM- 20240112
LR  - 20240113
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 25
IP  - 1
DP  - 2023 Dec 19
TI  - Everolimus Acts in Synergy with Vinorelbine to Suppress the Growth of 
      Hepatocellular Carcinoma.
LID - 10.3390/ijms25010017 [doi]
LID - 17
AB  - Hepatocellular carcinoma (HCC) is a challenging cancer to treat, as traditional 
      chemotherapies have shown limited effectiveness. The mammalian target of 
      rapamycin/sirolimus (mTOR) and microtubules are prominent druggable targets for 
      HCC. In this study, we demonstrated that co-targeting mTOR using mTOR inhibitors 
      (everolimus and sirolimus) along with the microtubule inhibitor vinorelbine 
      yielded results superior to those of the monotherapies in HCC PDX models. Our 
      research showed that the vinorelbine arrests cells at the mitotic phase, induces 
      apoptosis, and normalizes tumor blood vessels but upregulates survivin and 
      activates the mTOR/p70S6K/4EBP1 pathway. The addition of the everolimus 
      significantly improved the tumor response to the vinorelbine, leading to improved 
      overall survival (OS) in most tested orthotopic HCC PDX models. The mechanistic 
      investigation revealed that this marked antitumor effect was accompanied by the 
      downregulations of mTOR targets (p-p70S6K, p-4EBP1, and p-S6K); several key 
      cell-cycle regulators; and the antiapoptotic protein survivin. These effects did 
      not compromise the normalization of the blood vessels observed in response to the 
      vinorelbine in the vinorelbine-sensitive PDX models or to the everolimus in the 
      everolimus-sensitive PDX models. The combination of the everolimus and 
      vinorelbine (everolimus/vinorelbine) also promoted apoptosis with minimal 
      toxicity. Given the cost-effectiveness and established effectiveness of 
      everolimus, and especially sirolimus, this strategy warrants further 
      investigation in early-phase clinical trials.
FAU - Huynh, Hung
AU  - Huynh H
AD  - Laboratory of Molecular Endocrinology, National Cancer Centre Singapore, 
      Singapore 168583, Singapore.
FAU - Ng, Wai Har
AU  - Ng WH
AUID- ORCID: 0000-0002-0069-1599
AD  - Laboratory of Molecular Endocrinology, National Cancer Centre Singapore, 
      Singapore 168583, Singapore.
FAU - Soo, Khee Chee
AU  - Soo KC
AD  - Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, 
      Singapore 168583, Singapore.
LA  - eng
GR  - NMRC/MOHIAFCAT2/006/2016/National Medical Research Council/
GR  - CG21APR1005/National University Hospital/
GR  - CGAug16M005/RIE2020 NCIS Centre Grant/
GR  - NRF-CRP17-2017-05/National Research Foundation/
GR  - AM/TP049/2021/SingHealth DUKE-NUS Academic Medicine Research Grant/
PT  - Journal Article
DEP - 20231219
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 9HW64Q8G6G (Everolimus)
RN  - Q6C979R91Y (Vinorelbine)
RN  - 0 (Survivin)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Humans
MH  - Everolimus/pharmacology
MH  - *Carcinoma, Hepatocellular/drug therapy
MH  - Vinorelbine/pharmacology
MH  - Survivin
MH  - Ribosomal Protein S6 Kinases, 70-kDa
MH  - *Liver Neoplasms/drug therapy
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
PMC - PMC10779360
OTO - NOTNLM
OT  - hepatocellular carcinoma
OT  - hypoxia
OT  - mTOR inhibitor
OT  - microtubule inhibitor
OT  - vessel normalization
COIS- The authors declare no conflict of interest.
EDAT- 2024/01/11 07:43
MHDA- 2024/01/12 06:43
PMCR- 2023/12/19
CRDT- 2024/01/11 01:16
PHST- 2023/11/15 00:00 [received]
PHST- 2023/12/14 00:00 [revised]
PHST- 2023/12/15 00:00 [accepted]
PHST- 2024/01/12 06:43 [medline]
PHST- 2024/01/11 07:43 [pubmed]
PHST- 2024/01/11 01:16 [entrez]
PHST- 2023/12/19 00:00 [pmc-release]
AID - ijms25010017 [pii]
AID - ijms-25-00017 [pii]
AID - 10.3390/ijms25010017 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Dec 19;25(1):17. doi: 10.3390/ijms25010017.