Targeting apoptosis to overcome cisplatin resistance: a translational study in head and neck cancer.
OBJECTIVE
Cisplatin resistance remains a barrier to organ-sparing and survival of patients with advanced head and neck squamous cell carcinoma (HNSCC). Targeted therapies to overcome cisplatin-resistant HNSCC are being developed.


METHODS
Cisplatin-sensitive parental HNSCC cell lines and cisplatin-resistant progeny were studied. Pretreatment HNSCC biopsies were used to construct tissue microarrays which were stained for p53 and Bcl-xL.


RESULTS
HNSCC cell lines selected for cisplatin resistance had wild-type p53 and high levels of Bcl-xL. Expression of wild-type p53 in cell lines with low Bcl-xL enhanced cisplatin sensitivity. Expression of both Bcl-xL and wild-type p53 caused tumor cells to become cisplatin resistant. Patients whose tumors expressed low levels of p53 and Bcl-xL enjoyed the best organ preservation and disease-free survival whereas patients whose tumors expressed low levels of p53 and high levels of Bcl-xL had the worst outcome. Novel agents that inhibit Bcl-xL or activate p53 function may target cisplatin-resistant HNSCC.


CONCLUSIONS
Cisplatin resistance in HNSCC is mediated, at least in part, by high Bcl-xL and functional p53.
Bauer
Joshua A
JA
Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA.
Kumar
Bhavna
B
Cordell
Kitrina G
KG
Prince
Mark E
ME
Tran
Huong H
HH
Wolf
Gregory T
GT
Chepeha
Douglas B
DB
Teknos
Theodoros N
TN
Wang
Steven
S
Eisbruch
Avraham
A
Tsien
Christina I
CI
Urba
Susan G
SG
Worden
Francis P
FP
Lee
Julia
J
Griffith
Kent A
KA
Taylor
Jeremy M G
JM
D'Silva
Nisha
N
Wang
Shaomeng J
SJ
Wolter
Keith G
KG
Henson
Bradley
B
Fisher
Susan G
SG
Carey
Thomas E
TE
Bradford
Carol R
CR
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000532:radiotherapy; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046888:Tissue Array Analysis / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D002945:Cisplatin