15-Deoxy-Delta12,14-prostaglandin J2 enhances docetaxel anti-tumor activity against A549 and H460 non-small-cell lung cancer cell lines and xenograft tumors.
15-Deoxy-Delta-prostaglandin J2 is a naturally occurring endogenous ligand for peroxisome proliferator-activated receptor-gamma. The current study was aimed to determine the mechanism of anti-proliferative effect of 15-deoxy-Delta-prostaglandin J2+docetaxel against A549 and H460 non-small-cell lung cancer cell lines and xenograft tumors. In-vitro cytotoxicity of 15-deoxy-Delta-prostaglandin J2 alone and in combination with docetaxel was studied against A549 and H460 cell lines. For in-vivo studies, female athymic nu/nu mice were xenografted with A549 and H460 tumors and treated with 15-deoxy-Delta-prostaglandin J2 (1 mg/kg/day; intraperitoneal), docetaxel (10 mg/kg; intravenous on days 14, 18 and 22) and 15-deoxy-Delta-prostaglandin J2+docetaxel. Apoptosis was measured in A549 cells and tumor tissues, following various treatments. Peroxisome proliferator-activated receptor-gamma, caspases, Bcl2 and p53 family proteins or their mRNA expressions were measured by Western blotting, reverse transcription-polymerase chain reaction and real-time polymerase chain reaction in A549 tumors. A possible role of a peroxisome proliferator-activated receptor-gamma-independent mechanism was studied in A549 cells treated with peroxisome proliferator-activated receptor-gamma antagonist, GW9662. Isobolographic analysis demonstrated synergistic interaction (combination index <1.0) between 15-deoxy-Delta-prostaglandin J2 and docetaxel against A549 and H460 cells in vitro. 15-Deoxy-Delta-prostaglandin J2+docetaxel significantly reduced the tumor volume compared with control (P<0.05), 15-deoxy-Delta-prostaglandin J2 (P<0.05) and docetaxel (P<0.05, P<0.01) in both A549 and H460 tumors. 15-Deoxy-Delta-prostaglandin J2+docetaxel showed a significant increase in apoptosis associated with inhibition of the Bcl2 and cyclin D1 expression and overexpression of caspase and p53 pathway genes. Further, enhanced expression of caspase 3 and inhibition of cyclin D1 by 15-deoxy-Delta-prostaglandin J2+docetaxel was not reversed by GW9662, thus suggesting a possible peroxisome proliferator-activated receptor-gamma-independent mechanism. In conclusion, 15-deoxy-Delta-prostaglandin J2 enhanced the anti-tumor action of docetaxel by peroxisome proliferator-activated receptor-gamma-dependent and -independent mechanisms mediated by induction of apoptosis.
Fulzele
Suniket V
SV
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee FL 32307, USA.
Chatterjee
Abhijit
A
Shaik
Madhu Sudhan
MS
Jackson
Tanise
T
Ichite
Nkechi
N
Singh
Mandip
M
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D053148:Caspase 3 / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D047495:PPAR gamma / Q000187:drug effects*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000970:Antineoplastic Agents; D007155:Immunologic Factors; D047495:PPAR gamma; D043823:Taxoids; D000077143:Docetaxel; D053148:Caspase 3; D015230:Prostaglandin D2