PMID- 38052108
OWN - NLM
STAT- MEDLINE
DCOM- 20240219
LR  - 20240310
IS  - 1095-6859 (Electronic)
IS  - 0090-8258 (Print)
IS  - 0090-8258 (Linking)
VI  - 180
DP  - 2024 Jan
TI  - Manipulation of metabolic responses enhances SHetA2 efficacy without toxicity in 
      cervical cancer cell lines and xenografts.
PG  - 44-54
LID - S0090-8258(23)01558-5 [pii]
LID - 10.1016/j.ygyno.2023.11.013 [doi]
AB  - OBJECTIVE: The high frequency of cervical cancer recurrence after primary therapy 
      necessitates alternative treatments. High-risk human papillomavirus (HR-HPV) 
      causes cervical cancer and it's continued presence supports elevated metabolism, 
      proliferation and survival of cancer cells. The low-to-no toxicity new 
      investigational drug, SHetA2, counteracts high-risk human papillomavirus (HR-HPV) 
      effects on cell proliferation and survival in cervical cancer cells and xenograft 
      tumors by disrupting heat shock protein 70 chaperone protection of oncogenic 
      proteins. Our objective was to study the involvement of metabolism in SHetA2 
      effects on cervical cancer cells and tumors. METHODS: SHetA2-mediated proteomic 
      and metabolic effects were measured in HR-HPV-positive CaSKi and SiHa and 
      HR-HPV-negative C-33 A cervical cancer cell lines. Combined treatment with 
      2-deoxyglucose (2-DG) was evaluated in cell culture and SiHa xenografts. RESULTS: 
      SHetA2 inhibited oxidative phosphorylation (OxPhos) and altered levels of 
      proteins involved in metabolism, protein synthesis, and DNA replication and 
      repair. Cervical cancer cells responded by elevating glycolysis. Inhibition of 
      the glycolytic responses using galactose media or 2-DG increased SHetA2 
      sensitivity of two HR-HPV-positive, but not an HR-HPV-negative cervical cancer 
      cell line. Interaction of 2-DG and SHetA2 was synergistic in HR-HPV positive cell 
      lines in association with augmentation of SHetA2 ATP reduction, but not SHetA2 
      DNA damage induction. These results were verified in a SiHa xenograft tumor model 
      without evidence of toxicity. CONCLUSIONS: Compensatory glycolysis counteracts 
      OxPhos inhibition in SHetA2-treated HR-HPV-positive cervical cancer cell lines. 
      Prevention of compensatory glycolysis with 2-DG or another glycolysis inhibitor 
      has the potential to improve SHetA2 therapy without toxicity.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Rai, Rajani
AU  - Rai R
AD  - Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, 
      Stephenson Cancer Center, University of Oklahoma Health Sciences Center, USA.
FAU - Lightfoot, Stanley
AU  - Lightfoot S
AD  - Department of Pathology, University of Oklahoma Health Sciences Center, USA.
FAU - Benbrook, Doris Mangiaracina
AU  - Benbrook DM
AD  - Section of Gynecologic Oncology, Department of Obstetrics and Gynecology, 
      Stephenson Cancer Center, University of Oklahoma Health Sciences Center, USA. 
      Electronic address: Doris-Benbrook@ouhsc.edu.
LA  - eng
GR  - P30 CA225520/CA/NCI NIH HHS/United States
GR  - R01 CA200126/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20231205
PL  - United States
TA  - Gynecol Oncol
JT  - Gynecologic oncology
JID - 0365304
RN  - 0 ((((4-nitrophenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) 
      methane-1-thione)
RN  - 0 (Chromans)
RN  - 0 (Thiones)
SB  - IM
MH  - Female
MH  - Humans
MH  - *Uterine Cervical Neoplasms/pathology
MH  - Heterografts
MH  - Cell Line, Tumor
MH  - *Papillomavirus Infections/complications/drug therapy
MH  - Proteomics
MH  - Neoplasm Recurrence, Local
MH  - *Chromans
MH  - *Thiones
PMC - PMC10922646
MID - NIHMS1949548
OTO - NOTNLM
OT  - 2-deoxyglucose
OT  - Cervical cancer
OT  - Compensatory glycolysis
OT  - Oxidative phosphorylation
OT  - SHetA2
COIS- Declaration of Competing Interest The authors declare no competing interests.
EDAT- 2023/12/06 03:41
MHDA- 2024/02/19 06:44
PMCR- 2025/01/01
CRDT- 2023/12/05 18:00
PHST- 2023/10/12 00:00 [received]
PHST- 2023/11/10 00:00 [revised]
PHST- 2023/11/12 00:00 [accepted]
PHST- 2025/01/01 00:00 [pmc-release]
PHST- 2024/02/19 06:44 [medline]
PHST- 2023/12/06 03:41 [pubmed]
PHST- 2023/12/05 18:00 [entrez]
AID - S0090-8258(23)01558-5 [pii]
AID - 10.1016/j.ygyno.2023.11.013 [doi]
PST - ppublish
SO  - Gynecol Oncol. 2024 Jan;180:44-54. doi: 10.1016/j.ygyno.2023.11.013. Epub 2023 
      Dec 5.