Nitric oxide improves cisplatin cytotoxicity in head and neck squamous cell carcinoma.
OBJECTIVE
To test whether nitric oxide (NO) enhances the cytotoxicity of cisplatin in a head and neck squamous cell carcinoma (HNSCC) cell line.


BACKGROUND
Cisplatin is one of the most frequently used chemotherapeutic agents in the treatment of HNSCC. NO has been shown to play an important role in regulating tumor growth. Previous studies demonstrate that NO can enhance the cytotoxicity of cisplatin in Chinese hamster lung fibroblasts. In this report, we examined the in vitro interaction of NO and cisplatin in a HNSCC cell line.


METHODS
CCL23 cells were pretreated with three different NO donors: PAPA/NO (t 1/2 = 15 min), DPTA/NO (t 1/2 = 3 h), and DETA/NO (t 1/2 = 20 h). The cells were rinsed and exposed for 6 hours to a culture medium containing cisplatin. Cell survival and LD50 of cisplatin were calculated with and without NO pretreatment.


RESULTS
PAPA/NO and DPTA/NO did not show any cytotoxic activity and did not change the LD50 of cisplatin. DETA/NO when used alone resulted in 25.6% cell death at its peak dose (100 microM). Pretreatment with DETA/NO resulted in almost a threefold reduction of the LD50 of cisplatin (6.8 vs. 2.4 microg/mL). Pretreatment with DETA/NO sensitized the HNSCC cells to subsequent cisplatin activity (two-sided P =.00016).


CONCLUSIONS
Pretreatment of HNSCC cells with long-acting NO donors enhances cisplatin activity. Short- and medium-acting NO donors do not exert a toxic effect and do not augment the activity of cisplatin. NO agonists should be considered in the future as a possible adjunct to cisplatin in the treatment of HNSCC. Further studies with animal models are necessary to further clarify this relationship.
Azizzadeh
B
B
Division of Head and Neck Surgery, Department of Molecular and Medical Pharmacology, University of California Los Angeles School of Medicine, Los Angeles, California 90095-1624, USA.
Yip
H T
HT
Blackwell
K E
KE
Horvath
S
S
Calcaterra
T C
TC
Buga
G M
GM
Ignarro
L J
LJ
Wang
M B
MB
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002460:Cell Line; D002470:Cell Survival; D002945:Cisplatin / Q000633:toxicity*; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology
D000970:Antineoplastic Agents; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D002945:Cisplatin