Impact and mechanism of non-steroidal anti-inflammatory drugs combined with chemotherapeutic drugs on human lung cancer-nude mouse transplanted tumors

Abstract

Abstract. The present study aimed to investigate the impact of indomethacin treatment combined with oxaliplatin treatment on the expression of cluster of differentiation 44 variant 6 (CD44v6), matrix metalloproteinase-2 (MMP-2) and survivin in human lung cancer-nude mouse transplanted tumors. The human lung adenocarcinoma (A549)-nude mouse transplanted tumor model was established, and the mice were divided into a control group, an indomethacin treatment group, an oxaliplatin treatment group and an indomethacin-oxaliplatin combination treatment group. The tumor inhibition rate was calculated following sacrificing of the mice. Immunohistochemical staining and fluorescence reverse transcription-quantitative polymerase chain reaction were utilized to detect the protein and messenger (m)RNA expression of CD44v6, MMP-2 and survivin. The tumor inhibition rates of the indomethacin group, the oxaliplatin group and the combination group were 26.67, 47.70 and 68.88%, respectively. The protein and mRNA expression levels of CD44v6, MMP-2 and survivin in the transplanted tumors of each treatment group were reduced compared with the control group (P<0.05), and those of the combination group were lower compared with the single-drug treatment groups (P<0.05). Survivin and MMP-2, MMP-2 and CD44v6, and MMP-2 and CD44v6 all exhibited linear positive correlation. The present study provides evidence that the administration of indomethacin alone, or in combination with oxaliplatin, may significantly inhibit the growth of lung cancer-nude mouse transplanted tumors and the expression of CD44v6, MMP-2 and survivin inside the tumor. The combination of non-steroidal anti-inflammatory drugs with chemotherapeutic drugs may improve the antitumor effects.

Indomethacin Disrupts Autophagic Flux by Inducing Lysosomal Dysfunction in Gastric Cancer Cells and Increases Their Sensitivity to Cytotoxic Drugs

“…It seems, therefore, that oxaliplatin promotes autophagy in these gastric cancer cells and that indomethacin, alone and especially in the presence of chloroquine, inhibits the degradation of the newly formed autophagosomes. When we added indomethacin to the culture media after a period in the presence of oxaliplatin, this NSAID enhanced the toxic effect of oxaliplatin and produced a concomitant decrease in autophagic activity, which may explain the synergy observed between the two drugs in the present study and previously in an in vivo model of cancer 26 . Thus, inhibition of lysosomal function and the consequent interference with autophagic degradation may be partly responsible for the beneficial effects of indomethacin in cancerous processes reported in some studies 4 , 26 , 27 .…”

Pt(IV) Prodrugs with NSAIDs as Axial Ligands

“…The MMP-9 inhibitory activity of prodrug 17 was evaluated by immunohistochemical staining using slices of CT-26 mice tumors in comparison with the effect of oxaliplatin and saline. Compound 17 showed significant inhibition of MMP-9 expression (6.8%), while oxaliplatin inhibition level was 8.1%, in accordance with the literature data [ 41 ]. The observed difference in inhibitory activity is associated with the presence of the naproxen moiety in prodrug 17 .…”

Valproic acid inhibit non-small-cell lung cancer (A549 cell line) metastasis via inhibition of CD44v6 and Nm23H1

“…Among all isoforms, CD44v6 contains a mutation of exon 11 and plays an important role in enhancing the adhesive ability of tumor cells [24]. An evidence-based report showed that an increase in the expression of CD44v6 altered the physiochemical properties of tumor cells and increased their metastatic potential [25]. The present study showed that the expression of CD44v6 protein and mRNA were concentration dependent on VPA, which demonstrated the inhibitory effect of VPA on tumorigenesis.…”