NSAIDs induce apoptosis in nonproliferating ovarian cancer cells and inhibit tumor growth in vivo

Abstract

Ovarian cancer (OC) is one of the most lethal gynaecological cancers, which usually has a poor prognosis due to late diagnosis. A large percentage of the OC cell population is in a nonproliferating and quiescent stage, which poses a barrier to success when using most chemotherapeutic agents. Recent studies have shown that several nonsteroidal anti‐inflammatory drugs (NSAIDs) are effective in the treatment of OC. Furthermore, we have previously described the molecular mechanisms of NSAIDs' induction of cancer apoptosis. In this report, we evaluated various structurally distinct NSAIDs for their efficacies in inducing apoptosis in nonproliferating OC cells. Although several NSAIDs‐induced apoptosis, Flufenamic Acid, Flurbiprofen, Finasteride, Celocoxib, and Ibuprofen were the most potent NSAIDs inducing apoptosis. A combination of these agents resulted in an enhanced effect. Furthermore, we demonstrate that the combination of Flurbiprofen, which targets nonproliferative cells, and Sulindac Sulfide, that affects proliferative cells, strongly reduced tumor growth when compared with a single agent treatment. Our data strongly support the hypothesis that drug treatment regimens that target nonproliferating and proliferating cells may have significant efficacy against OC. These results also provide a rationale for employing compounds or even chemically modified NSAIDs, which selectively and efficiently induce apoptosis in cells during different stages of the cell cycle, to design more potent anticancer drugs. © 2012 IUBMB IUBMB Life, 64(7): 636–643, 2012

Investigation of flurbiprofen genotoxicity and cytotoxicity in rat bone marrow cells

“…Similarly, it was claimed that flurbiprofen was one of the powerful NSAID inducer of apoptosis in ovarian cancer cells. Also, combination of sulindac sulfide targeting proliferative cells and flurbiprofen targeting nonproliferative cells weakened tumor growth more powerfully and effectively as compared with these substances in single form (Duncan et al, 2012). Similar to many of the mentioned findings, it has been reported that r-flurbiprofen inhibited colon adenomas in mice, reduced proliferation in pituitary adenoma cells in vitro and induced apoptosis (Liu et al, 2012).…”

“…Again, a study showed that flurbiprofen induced LDH release associated with cytotoxicity in monolayer rat hepatocytes culture (Jurima-Romet et al, 1994;Masubuchi et al, 1998). Flurbiprofen induced apoptosis in human polymorphonuclear neutrophils (Zielinska-Przyjemska et al, 2008), did not protect from oxidative stress induced by aluminum in rats (Nivsarkar et al, 2008) and reduced the growth of ovarian tumors (Duncan et al, 2012). After a comprehensive investigation, it was indicated that mutagenicity studies of flurbiprofen are not sufficient.…”

3d metal complexes with meloxicam as therapeutic agents in the fight against human glioblastoma multiforme and cervical carcinoma

“…[10,11] In recent years, there has been an increased interest in the antitumour activity of NSAIDs due to at least three reasons: (1) COX-2 is found to be overexpressed in many cancers thus making it an attractive therapeutic target for the prevention and treatment of a number of malignancies [11,12]; (2) chronic inflammation has been proved to play an important role in cancer development and progression [13,14]; (3) NSAIDs are used also by oncology patients and the 'relationships' between these drugs and cancer cells have to be better clarified. [15] Numerous studies have suggested that aspirin and/or other NSAIDs can be effective in the prevention and/or treatment of malignancies, such as cancers of the colon, [16] breast, [17,18] lung, [19] pancreas, [20] prostate, [21,22] ovarium, [23] squamous cell carcinoma and melanoma, [24] etc. Different NSAIDs have been reported to inhibit the growth and survival of cell lines established from a wide variety of cancers, including gastric cancer, [25,26] cancers of the colon, [27] lung, [28] urinary bladder, [29] osteosarcoma, [30] etc.…”

Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer

“…Other non-opiate therapies that have been shown to reduce CIBP and disease progression in preclinical models of bone cancer are NSAIDS and inhibitors of COX-2 3,11,21,22,45,48 . Both these therapies have also been shown to slow the growth of a wide variety of cancers and are commonly used as a first line therapy to treat CIBP 3,11,21,22,45,48 .…”