TY - JOUR
T1 - CDK4/6 inhibition on glucose and pancreatic beta cell homeostasis in young and aged rats
AU - Sacaan, Aida I.
AU - Thibault, Stephane
AU - Hong, Miyoun
AU - Kondegowda, Nagesha G.
AU - Nichols, Tim
AU - Li, Rosemary
AU - Rosselot, Carolina
AU - Evering, Winston
AU - Fenutria, Rafael
AU - Vitsky, Allison
AU - Brown, Thomas
AU - Finkelstein, Martin
AU - Garcia-Ocaña, Adolfo
AU - Khan, Nasir
AU - Stewart, Andrew F.
AU - Vasavada, Rupangi C.
N1 - Funding Information:
T. Brown is a research fellow at, reports receiving a commercial research grant from, and other commercial research support from Pfizer Drug Safety. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
The studies conducted at the Icahn School of Medicine at Mount Sinai were funded by a research contract from Pfizer Inc. Rat islets were isolated by the Human Islet and Adenovirus Core of the Einstein-Mount Sinai Diabetes Research Center (NIH-NIDDK P30 DK020541-38).
Publisher Copyright:
©2017 AACR.
PY - 2017/11
Y1 - 2017/11
N2 - Genetic deletion of cyclin-dependent kinase 4 (Cdk4) is associated with pancreatic beta cell loss and glucose dysregulation in rodents. Palbociclib, one of the first selective CDK4/6 inhibitors approved for the treatment of advanced breast cancer, is currently being investigated as an adjuvant treatment in patients with early-stage breast cancer and in a variety of cancers covering a wide-range of patient populations. Hence, longer chronic toxicity studies were necessary to further examine its safety profile. The effects of different doses and duration of palbociclib administration on glucose and beta cell homeostasis in young (two months) versus aged (12 months) rats was compared. Glucose dysregulation, due to pancreatic beta cell degeneration, was observed in young rats administered the highest dose of palbociclib for 6 months. Abnormal pancreatic islet histology and activation of the endoplasmic reticulum stress response in beta cells were detected after shorter administration with high-dose palbociclib in young rats. To test the hypothesis that palbociclib-associated inhibition of beta cell proliferation will more profoundly affect younger animals that have not achieved replicative quiescence, we administered high-dose palbociclib to aged rats for 6 months. In contrast to the young rats, despite equivalent exposures to palbociclib, no evidence of impaired glucose tolerance, hypoinsulinemia, beta cell vacuolization, or beta cell loss was seen in aged rats. Palbociclib administration induces beta cell failure in young but not aged rats.
AB - Genetic deletion of cyclin-dependent kinase 4 (Cdk4) is associated with pancreatic beta cell loss and glucose dysregulation in rodents. Palbociclib, one of the first selective CDK4/6 inhibitors approved for the treatment of advanced breast cancer, is currently being investigated as an adjuvant treatment in patients with early-stage breast cancer and in a variety of cancers covering a wide-range of patient populations. Hence, longer chronic toxicity studies were necessary to further examine its safety profile. The effects of different doses and duration of palbociclib administration on glucose and beta cell homeostasis in young (two months) versus aged (12 months) rats was compared. Glucose dysregulation, due to pancreatic beta cell degeneration, was observed in young rats administered the highest dose of palbociclib for 6 months. Abnormal pancreatic islet histology and activation of the endoplasmic reticulum stress response in beta cells were detected after shorter administration with high-dose palbociclib in young rats. To test the hypothesis that palbociclib-associated inhibition of beta cell proliferation will more profoundly affect younger animals that have not achieved replicative quiescence, we administered high-dose palbociclib to aged rats for 6 months. In contrast to the young rats, despite equivalent exposures to palbociclib, no evidence of impaired glucose tolerance, hypoinsulinemia, beta cell vacuolization, or beta cell loss was seen in aged rats. Palbociclib administration induces beta cell failure in young but not aged rats.
UR - http://www.scopus.com/inward/record.url?scp=85032835765&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-17-0172
DO - 10.1158/1541-7786.MCR-17-0172
M3 - Article
C2 - 28760782
AN - SCOPUS:85032835765
SN - 1541-7786
VL - 15
SP - 1531
EP - 1541
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 11
ER -