Etodolac induces apoptosis and inhibits cell adhesion to bone marrow stromal cells in human myeloma cells

Nakamura, Satoki; Kobayashi, Miki; Shibata, Kiyoshi; Sahara, Naohi; Shigeno, Kazuyuki; Shinjo, Kaori; Naito, Kensuke; Hayashi, Hideharu; Ohnishi, Kazunori

doi:10.1016/j.leukres.2005.06.009

« Previous Next »Leukemia Research
Volume 30, Issue 2 , Pages 123-135, February 2006

Etodolac induces apoptosis and inhibits cell adhesion to bone marrow stromal cells in human myeloma cells

Satoki Nakamura
- Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan
- Corresponding author. Tel.: +81 53 435 2267; fax: +81 53 434 2910.
Miki Kobayashi
- Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan
Kiyoshi Shibata
- Research Equipment Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan
Naohi Sahara
- Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan
Kazuyuki Shigeno
- Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan
Kaori Shinjo
- Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan
Kensuke Naito
- Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan
Hideharu Hayashi
- Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan
Kazunori Ohnishi
- Department of Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan

Received 21 December 2004; received in revised form 17 June 2005; accepted 18 June 2005. published online 07 March 2011.

Abstract

Objectives

Cyclooxygenase-2 (COX-2) is reported to regulate apoptosis and to be an important cellular target for therapy.

Methods

We examined whether etodolac, meloxicam, and thalidomide inhibited proliferation and induced apoptosis in myeloma cell lines (RPMI 8226 and MC/CAR cells).

Results

Etodolac induced apoptosis more strongly compared with thalidomide or meloxicam. Etodolac induced down-regulation of Bcl-2 protein and mRNA, activation of Caspase-9, -7 and -3, cIAP-1 and Survivin, and loss of mitochondrial membrane potential in a dose-dependent manner. In addition, when myeloma cells were coincubated with 50μM etodolac on bone marrow stromal cells (BMSCs), myeloma cell adhesion to BMSCs was significantly inhibited compared with thalidomide or meloxicam coincubation, and the adhesion molecules VLA-4, LFA-1 (CD11a), CXCX4, and CD44 were suppressed on myeloma cells treated with etodolac. Moreover, 50–100μM racemate of etodolac significantly inhibited the proliferation of myeloma cells compared to 100μM R-etodolac or S-etodolac.

Conclusions

Etodolac induced loss of mitochondrial membrane potential and apoptosis via a COX-2-independent pathway, suppressed the expression of adhesion molecules, and inhibited myeloma cell adhesion to BMSCs compared with thalidomide or meloxicam. The activities of etodolac potentially extend to the treatment of patients with myeloma resistant to standard chemotherapy, including thalidomide.

Keywords: Etodolac, Myeloma, Apoptosis, Bcl-2, Cell adhesion