Combination of celecoxib and doxorubicin increases growth inhibition and apoptosis in acute myeloid leukemia cells

Abstract

Cyclooxygenase-2 (COX-2) inhibitors have been shown to enhance antitumor activity of therapeutic agents in a variety of solid tumor cells. However, this has not been well established in hematopoietic tumors, especially in acute myeloid leukemia (AML). This study was designed to investigate the effects of the combination of celecoxib, a specific COX-2 inhibitor, and doxorubicin on cell growth and apoptosis in human leukemia cells. Co-treatment with celecoxib and doxorubicin significantly inhibited cell growth and induced cell apoptosis in the acute leukemia cell line HL60 and primary AML cells. The growth inhibition effect was accompanied by down-regulation of the expression of cyclin E and cyclin-dependent kinase 2 (CDK2), the key regulators of cell cycle progression, which was associated with arrest of cells at G0/G1 phase. The pro-apoptotic effect was accompanied by down-regulation of the expression of survivin, an inhibitor of apoptosis protein, which mediated anti-apoptosis in AML cells. These results provide the first evidence that the growth inhibitory and pro-apoptotic effects of celecoxib and doxorubicin on AML cells are synergistic.

Celecoxib inhibits mitochondrial O2 consumption, promoting ROS dependent death of murine and human metastatic cancer cells via the apoptotic signalling pathway

“…In these studies, the metastatic cancer cells were only exposed to a single dose of drug added at the start of the assays, with monitoring over periods of 24-72 h. Repeated daily doses of low (1-10 µM) celecoxib levels administered to the metastatic cancer cells could sustain much higher accumulative drug actions and effects in vitro, with a greater net cytotoxic activity and further decrease IC 50 and GI 50 values in a system more closely mimicking an in vivo dosing regimen [43]. In this regard, low and physiologically relevant levels (1-10 µM) of celecoxib have been reported to chemosensitize cancer cells to subsequent treatment with common cytotoxic chemotherapeutic drugs such as doxorubicin [44,45] and greatly enhances chemotherapeutic anti-metastatic cancer cell efficacy in vitro and in vivo [44,46], as well as in clinical trials of metastatic colorectal cancer patients [42].…”

Raised CD40L expression attenuates drug resistance in Adriamycin‑resistant THP‑1 cells

“…ADM (23) and DNR (24) are important and commonly-used drugs in the clinical treatment of AML. In this study, THP-1 cells were rendered resistant to ADM (THP-1/A cells) and…”

Cancer stem cells, stemness markers and selected drug targeting: metastatic colorectal cancer and cyclooxygenase-2/prostaglandin E2 connection to WNT as a model system

“…Although many of the NSAIDs show similar properties and ability to act as cytotoxic anticancer drugs (reviewed in [194] ), celecoxib was found to be by far the most outstanding [23,193] and was highly effective at inhibiting growth of triple negative breast cancer spheroids [195] . In this regard, in many animal models of cancer, celecoxib has been shown to chemosensitize cancer cells in a synergistic manner to enhance the cytotoxic effects of commonly used chemotherapies, such as the anthracycline drugs doxorubicin and epirubicin [196][197][198][199][200] and platinum-based chemotherapies [164,199,[201][202][203][204][205][206] . In murine models of colorectal cancer, synergistic anticancer effects were obtained by combining celecoxib with the common CRC chemotherapeutic drug, 5-fluorouracil (5-FU) [207] or with oxaliplatin [208] .…”