A randomized phase II study investigating the addition of the specific COX-2 inhibitor celecoxib to docetaxel plus carboplatin as first-line chemotherapy for stage IC to IV epithelial ovarian cancer, Fallopian tube or primary peritoneal carcinomas: the DoCaCel study

Reyners, An; Munck, Linda de; Erdkamp, Frans; Smit, Willem M.; Hoekman, K.; Lalisang, Roy I.; Graaf, Hiltje de; Wymenga, A.N.M.; Polée, Marco B.; Hollema, Harry; Vugt, Marcel A.T.M. van; Schaapveld, Michael; Willemse, Phb

doi:10.1093/annonc/mds107

Cited by 38 publications

(45 citation statements)

References 29 publications

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“…In ovarian cancer, cyclooxygenases are upregulated and have been considered as potential targets, however, clinical trials have been mixed and do not support significant benefit in combinatorial treatment with chemotherapy and a cyclooxygenase inhibitor versus treatment with chemotherapy alone (31). Although the survival benefit of ketorolac use in breast cancer was postulated to be due to possible inhibitory roles in anti-angiogenesis, inhibition of prostaglandin synthesis and decreased immune suppression as compared to opioids and other analgesics (51), there was previously no precedence for other pharmacologic activities associated with R- or S-ketorolac.…”

Section: Discussionmentioning

confidence: 99%

“…Published literature on breast, lung and kidney cancer patients and our own data on ovarian cancer patients demonstrates that besides its analgesic function, ketorolac has significant benefit for patient survival (6, 12, 29, 30). The mechanism of this anti-cancer action is not clear, yet appears to be selectively ascribed to ketorolac and not a general property of cyclooxygenase inhibitors or other analgesics and anesthetics (6, 31, 32). This suggests that ketorolac possesses an additional property.…”

Section: Introductionmentioning

confidence: 99%

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R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis

Guo

Kenney

Muller

et al. 2015

Molecular Cancer Therapeutics

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Cdc42 (cell division control protein 42) and Rac1 (Ras-related C3 botulinum toxin substrate 1) are attractive therapeutic targets in ovarian cancer based on established importance in tumor cell migration, adhesion and invasion. Despite a predicted benefit, targeting GTPases has not yet been translated to clinical practice. We previously established that Cdc42 and constitutively active Rac1b are overexpressed in primary ovarian tumor tissues. Through high throughput screening and computational shape homology approaches we identified R-ketorolac as a Cdc42 and Rac1 inhibitor; distinct from the anti-inflammatory, cyclooxygenase inhibitory activity of S-ketorolac. In the present study, we establish R-ketorolac as an allosteric inhibitor of Cdc42 and Rac1. Cell-based assays validate R-ketorolac activity against Cdc42 and Rac1. Studies on immortalized human ovarian adenocarcinoma cells (SKOV3ip), and primary, patient-derived ovarian cancer cells show R-ketorolac is a robust inhibitor of growth factor or serum dependent Cdc42 and Rac1 activation with a potency and cellular efficacy similar to small molecule inhibitors of Cdc42 (CID2950007/ML141) and Rac1 (NSC23766). Furthermore, GTPase inhibition by R-ketorolac reduces downstream p21-activated kinases (PAK1/PAK2) effector activation by >80%. Multiple assays of cell behavior using SKOV3ip and primary patient-derived ovarian cancer cells show that R-ketorolac significantly inhibits cell adhesion, migration and invasion. In sum, we provide evidence for R-ketorolac as direct inhibitor of Cdc42 and Rac1 that is capable of modulating downstream GTPase-dependent, physiological responses, which are critical to tumor metastasis. Our findings demonstrate the selective inhibition of Cdc42 and Rac1 GTPases by an FDA approved drug-racemic ketorolac that can be used in humans.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis

Guo

Kenney

Muller

et al. 2015

Molecular Cancer Therapeutics

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“…For example, a study of advanced epithelial ovarian cancer treated with docetaxel, carboplatin using adjuvant celecoxib at 400 mg twice daily showed no survival benefit from added celecoxib [129]. We refer to the reciprocal relationship between COX and 5-LO, discussed in detail with references in section 4. below as explanation for this failure and how we address this in CUSP9*.…”

Section: Introductionmentioning

confidence: 99%

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

Kast¹,

2014

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CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs- aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.

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“…Several studies suggested that Celecoxib could evoke cell cycle arrest, apoptosis, and anti-angiogenesis [9]. Therefore, a number of clinical trials have been performed to inspect the effect of Celecoxib on the adjuvant therapy of cancers such as non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and oral premalignant lesions, as well as in the treatment of EOC [10][11][12][13]. However, these trials demonstrated that using Celecoxib as adjuvant therapy failed to improve the prognosis of patients.…”

Section: Introductionmentioning

confidence: 99%

“…However, these trials demonstrated that using Celecoxib as adjuvant therapy failed to improve the prognosis of patients. Although a study on 45 recurrent patients with ovarian cancer treated with Celecoxib and carboplatin showed promising activity, another clinical trial on 151 patients with ovarian cancer who were treated with Celecoxib and docetaxel plus carboplatin showed no improvement in progression-free survival and overall survival [13,14]. The mechanisms of these controversial therapeutic effects of Celecoxib in ovarian cancer remain to be investigated.…”

Section: Introductionmentioning

confidence: 99%

Celecoxib induces epithelial-mesenchymal transition in epithelial ovarian cancer cells via regulating ZEB1 expression

Liu

Zheng

et al. 2014

Arch Gynecol Obstet

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A randomized phase II study investigating the addition of the specific COX-2 inhibitor celecoxib to docetaxel plus carboplatin as first-line chemotherapy for stage IC to IV epithelial ovarian cancer, Fallopian tube or primary peritoneal carcinomas: the DoCaCel study

Cited by 38 publications

References 29 publications

R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis

R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis

CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

Celecoxib induces epithelial-mesenchymal transition in epithelial ovarian cancer cells via regulating ZEB1 expression

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