PMID- 32429557
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210325
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 12
IP  - 5
DP  - 2020 May 17
TI  - Complementary Targeting of Rb Phosphorylation and Growth in Cervical Cancer Cell 
      Cultures and a Xenograft Mouse Model by SHetA2 and Palbociclib.
LID - 10.3390/cancers12051269 [doi]
LID - 1269
AB  - Cervical cancer is caused by high-risk human papillomavirus (HPV) types and 
      treated with conventional chemotherapy with surgery and/or radiation. HPV E6 and 
      E7 proteins increase phosphorylation of retinoblastoma (Rb) by cyclin D1/cyclin 
      dependent kinase (CDK)4/6 complexes. We hypothesized that cyclin D1 degradation 
      by the SHetA2 drug in combination with palbociclib inhibition of CDK4/6 activity 
      synergistically reduces phosphorylated Rb (phospho-Rb) and inhibits cervical 
      cancer growth. The effects of these drugs, alone, and in combination, were 
      evaluated in SiHa and CaSki HPV-positive and C33A HPV-negative cervical cancer 
      cell lines using cell culture, western blots and ELISA, and in a SiHa xenograft 
      model. Endpoints were compared by isobolograms, ANOVA, and Chi-Square. In all 
      cell lines, combination indexes documented synergistic interaction of SHetA2 and 
      palbociclib in association SHetA2 reduction of cyclin D1 and phospho-Rb, 
      palbociclib reduction of phospho-Rb, and enhanced phospho-Rb reduction upon drug 
      combination. Both drugs significantly reduced phospho-Rb and growth of SiHa 
      xenograft tumors as single agents and acted additively when combined, with no 
      evidence of toxicity. Dilated CD31-negative blood vessels adjacent to, or within, 
      areas of necrosis and apoptosis were observed in all drug-treated tumors. These 
      results justify development of the SHetA2 and palbociclib combination for 
      targeting phospho-Rb in cervical cancer treatment.
FAU - Kennedy, Amy L
AU  - Kennedy AL
AUID- ORCID: 0000-0002-7557-3909
AD  - Department of Pathology, College of Medicine, University of Oklahoma Health 
      Sciences Center, Oklahoma City, OK 73104, USA.
FAU - Rai, Rajani
AU  - Rai R
AUID- ORCID: 0000-0003-3503-5265
AD  - Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma 
      City, OK 73104, USA.
FAU - Isingizwe, Zitha Redempta
AU  - Isingizwe ZR
AD  - Department of Pharmaceutical Sciences, College of Pharmacy University of Oklahoma 
      Health Sciences Center, Oklahoma City, OK 73104, USA.
FAU - Zhao, Yan Daniel
AU  - Zhao YD
AD  - Department of Biostatistics and Epidemiology, College of Public Health University 
      of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
FAU - Lightfoot, Stanley A
AU  - Lightfoot SA
AD  - Center for Cancer Prevention and Drug Development, University of Oklahoma Health 
      Sciences Center, Oklahoma City, OK 73104, USA.
FAU - Benbrook, Doris M
AU  - Benbrook DM
AUID- ORCID: 0000-0001-7606-8245
AD  - Department of Pathology, College of Medicine, University of Oklahoma Health 
      Sciences Center, Oklahoma City, OK 73104, USA.
AD  - Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma 
      City, OK 73104, USA.
AD  - Department of Pharmaceutical Sciences, College of Pharmacy University of Oklahoma 
      Health Sciences Center, Oklahoma City, OK 73104, USA.
AD  - Department of Biostatistics and Epidemiology, College of Public Health University 
      of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
AD  - Center for Cancer Prevention and Drug Development, University of Oklahoma Health 
      Sciences Center, Oklahoma City, OK 73104, USA.
LA  - eng
GR  - P30 CA225520/CA/NCI NIH HHS/United States
GR  - R01 CA200126/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20200517
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC7281234
OTO - NOTNLM
OT  - SHetA2
OT  - cervical cancer
OT  - cyclin D1
OT  - palbociblib
OT  - retinoblastoma
COIS- The authors declare no conflict of interest.
EDAT- 2020/05/21 06:00
MHDA- 2020/05/21 06:01
PMCR- 2020/05/17
CRDT- 2020/05/21 06:00
PHST- 2020/04/23 00:00 [received]
PHST- 2020/05/08 00:00 [revised]
PHST- 2020/05/15 00:00 [accepted]
PHST- 2020/05/21 06:00 [entrez]
PHST- 2020/05/21 06:00 [pubmed]
PHST- 2020/05/21 06:01 [medline]
PHST- 2020/05/17 00:00 [pmc-release]
AID - cancers12051269 [pii]
AID - cancers-12-01269 [pii]
AID - 10.3390/cancers12051269 [doi]
PST - epublish
SO  - Cancers (Basel). 2020 May 17;12(5):1269. doi: 10.3390/cancers12051269.