Inhibitory effect of meloxicam, a selective cyclooxygenase‐2 inhibitor, and ciglitazone, a peroxisome proliferator‐activated receptor gamma ligand, on the growth of human ovarian cancers

Xin, Bing; Yokoyama, Yoshihiko; Shigeto, Tatsuhiko; Futagami, Masayuki; Mizunuma, Hideki

doi:10.1002/cncr.22854

Cited by 58 publications

(57 citation statements)

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“…(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) The present study has shown that meloxicam inhibited cell proliferation in situ, supported by our previous report where meloxicam inhibited proliferation of HepG2 cells in vitro. (31) Both studies have shown expression of PCNA, a key cell proliferation marker, was reduced by meloxicam.…”

Section: Discussionsupporting

confidence: 89%

“…(12,13) Selective COX-2 inhibitors have been regarded as a new group of anticancer drugs based on the observation that expression of COX-2 is elevated in a variety of human cancers (14)(15)(16)(17)(18) including HCC, (19,20) and COX-2 has been shown to promote growth and inhibit apoptosis of cancer cells. (21) A number of studies have investigated the use of meloxicam, a selective COX-2 inhibitor, in inhibiting growth of cancers of ovarian, (22) bladder, (23) biliary duct, (24) breast, (25) lung, (26) and colon. (27) Meloxicam has also shown anticancer activity to treat HCC in vitro and in vivo.…”

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confidence: 99%

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Combining kallistatin gene therapy and meloxicam to treat hepatocellular carcinoma in mice

Jiang

Qiao

et al. 2009

Cancer Science

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Hepatocellular carcinoma (HCC) is one of the most common cancerrelated causes of death, and conventional treatments offer unsatisfactory response. We have previously reported that kallistatin gene therapy suppressed the growth of HCC tumors by its antiangiogenic activity, and meloxicam, a selective COX-2 inhibitor, inhibited proliferation and induced apoptosis of human HCC cells in vitro. The aim of this study was to determine whether combining kallistatin gene therapy and meloxicam could offer a better therapeutic effect to combat HCC in mice. A kallistatin expression plasmid was constructed and its expression was detected after intratumoral gene transfer. Both kallistatin gene therapy and meloxicam suppressed the growth of subcutaneous human HepG2 tumors established in BALB ⁄ c nude mice, and the combinational therapy showed a stronger effect in suppressing tumor growth, tumor angiogenesis and cell proliferation, and increasing cell apoptosis, than the respective monotherapies. Gene transfer of kallistatin inhibited tumor angiogenesis, and slightly inhibited cell proliferation and increased cell apoptosis in situ, but had no effect on expression of vascular endothelial growth factor, basic fibroblast growth factor, proliferating cell nuclear antigen, Bcl-2, Bax, or activation of caspase-3. Meloxicam therapy inhibited cell proliferation, induced cell apoptosis, reduced expression of proliferating cell nuclear antigen, increased activation of caspase-3, and upregulated Bax. Meloxicam also slightly inhibited tumor angiogenesis with no effect on the expression of vascular endothelial growth factor or basic fibroblast growth factor. Combining two novel anticancer agents, kallistatin targeting tumoral vascularization and meloxicam targeting cell proliferation and apoptosis, warrants investigation as a therapeutic strategy to combat HCC. (Cancer Sci 2009; 100: 2226-2233 H epatocellular carcinoma is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide with an estimated incidence of over one million new cases each year.(1) Surgery offers a cure, but the rate of liver resection is <15% and recurrence rate remains as high as 50% after resection.(2) The conventional treatments including chemotherapy and radiotherapy offer unsatisfactory response. Therefore, new strategies to combat HCC are urgently needed.Solid tumors including HCC must establish an adequate vascular network to acquire necessary nutrition. Given that HCC is a hypervascular tumor, anti-angiogenic therapy offers a promising approach to treatment. Previous studies have revealed that angiogenesis inhibitors including TNP-470, (3) angiostatin, (4) endostatin, (5) soluble VEGF receptor 1,and vasostatin (6) are effective in treating HCC in experimental animal models. Kallistatin, a serine proteinase inhibitor, was first identified as a tissue kallikrein-binding protein,and has recently emerged as a novel inhibitor of angiogenesis. (8) Kallistatin inhibits the proliferation, migration, and adhesion of endothelial cells a...

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Section: Discussionsupporting

confidence: 89%

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confidence: 99%

Combining kallistatin gene therapy and meloxicam to treat hepatocellular carcinoma in mice

Jiang

Qiao

et al. 2009

Cancer Science

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“…The in vivo effects of meloxicam have also been reported, though not in detail (15)(16)(17). Since meloxicam has been widely used as an NSAID, its toxicity in humans as well as in animals is well known.…”

Section: Introductionmentioning

confidence: 99%

Antitumor effects of a cyclooxygenase-2 inhibitor, meloxicam, alone and in combination with radiation and/or 5-fluorouracil in cultured tumor cells

Ayakawa¹

2009

Mol Med Rep

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Abstract.To ascertain whether meloxicam used in a clinical setting as a non-steroidal anti-inflammatory drug (NSAID) warrants preclinical in vivo evaluation as an anticancer agent, we investigated its antitumor effects alone and in combination with radiation and/or 5-fluorouracil (5-FU) in cultured cells. Seven cell lines were examined for cyclooxygenase-2 (COX-2) protein expression by immunoblot analysis, and the HelaS3, SccVii and eMT6 cell lines were selected, expressing relatively high, intermediate, and relatively low COX-2 levels, respectively. Antitumor effects were examined using a colony assay. Among the three cell lines, the effect of meloxicam alone was strongest in SccVii cells. With 24 h of drug exposure, meloxicam at concentrations of 250 and 1250 µM had a definite antitumor effect, dependent on the drug exposure time. The effect of meloxicam in combination with radiation and/or 5-FU was also investigated in the SccVii cells. at a meloxicam concentration of 250 µM, the antitumor effect in combination with radiation or 5-FU was increased compared to the effect of radiation or 5-FU alone; however, the combined effect appeared to be additive. at lower concentrations, meloxicam had no radiosensitizing effect, nor did it enhance the effect of 5-FU. A meloxicam concentration of 250 µM is considerably higher than concentrations obtained in humans taking meloxicam as an nSaid. in conclusion, the antitumor effect of meloxicam was not correlated with the level of COX-2 protein expression. The effect of meloxicam in combination with radiation and/or 5-FU appeared to be additive. To evaluate the possibility of using meloxicam as an anticancer agent, in vivo investigations at clinically relevant drug dose levels are required.

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“…We also examined whether the addition of an NSAID to that regimen would further reduce osteophytic OA joint adaptations. The NSAID meloxicam is a selective cyclooxygenase 2 (COX-2) inhibitor (10), with known antiinflammatory and antiangiogenic effects (11)(12)(13). NSAIDs are prescribed primarily for the management of OA pain (14,15); however, they have also been found to have positive effects on cartilage health in OA by increasing proteoglycan and hyaluronan synthesis (16).…”

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confidence: 99%

In vivo microfocal computed tomography and micro–magnetic resonance imaging evaluation of antiresorptive and antiinflammatory drugs as preventive treatments of osteoarthritis in the rat

Jones

Tran

et al. 2010

Arthritis & Rheumatism

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Objective. To determine whether treatment with an antiresorptive drug in combination with an antiinflammatory drug reduces periarticular bone and soft tissue adaptations associated with the progression of posttraumatic secondary osteoarthritis (OA).Methods. We used in vivo microfocal computed tomography (micro-CT) to map bony adaptations and in vivo micro-magnetic resonance imaging (micro-MRI) to examine joint inflammation in a rat model of surgically induced OA secondary to knee triad injury. We examined the arthroprotective effects of the bisphosphonates alendronate and risedronate and the nonsteroidal antiinflammatory drug (NSAID) meloxicam.Results. Micro-CT revealed reduced levels of periarticular trabecular bone loss in animals with knee triad injury treated with the bisphosphonate drugs alendronate or risedronate, or the NSAID meloxicam, compared with untreated animals. Alendronate treatment reduced bony osteophyte development. While risedronate as a monotherapy did not positively impact osteophytogenesis, combination therapy with risedronate and meloxicam reduced osteophyte severity somewhat. Micro-MRI revealed an increased, diffuse water signal in the epiphyses of untreated rats with knee triad injury 8 weeks after surgery, suggestive of a bone marrow lesion-like stimulus. In contrast, meloxicamtreated rats showed a significant reduction in fluid signal compared with both bisphosphonate-treated groups 8 weeks after surgery. Histologic analysis qualitatively confirmed the chondroprotective effect of both bisphosphonate treatments, showing fewer degradative changes compared with untreated rats with knee triad injury.Conclusion. Our findings indicate that select combinations of bisphosphonate and NSAID drug therapy in the early stages of secondary OA preserve trabecular bone mass and reduce the impact of osteophytic bony adaptations and bone marrow lesion-like stimulus. Bisphosphonate and NSAID therapy may be an effective disease-modifying drug regimen if administered early after the initial injury.

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Inhibitory effect of meloxicam, a selective cyclooxygenase‐2 inhibitor, and ciglitazone, a peroxisome proliferator‐activated receptor gamma ligand, on the growth of human ovarian cancers

Cited by 58 publications

References 51 publications

Combining kallistatin gene therapy and meloxicam to treat hepatocellular carcinoma in mice

Combining kallistatin gene therapy and meloxicam to treat hepatocellular carcinoma in mice

Antitumor effects of a cyclooxygenase-2 inhibitor, meloxicam, alone and in combination with radiation and/or 5-fluorouracil in cultured tumor cells

In vivo microfocal computed tomography and micro–magnetic resonance imaging evaluation of antiresorptive and antiinflammatory drugs as preventive treatments of osteoarthritis in the rat

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