Both triazolyl ester of ketorolac (15K) and YM155 inhibit the embryonic angiogenesis &lt;i&gt;in ovo&lt;/i&gt; (fertilized eggs) &lt;i&gt;via&lt;/i&gt; their common PAK1-survivin/VEGF signaling pathway

Ahn, Mok-Ryeon; Bae, Jun Seok; Jeong, Dahye; Takahashi, Hideaki; Uto, Yoshihiro; Miyata, Hiroshi

doi:10.5582/ddt.2017.01058

Cited by 7 publications

(6 citation statements)

References 19 publications

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“…A 1,2,3-triazolyl ester of ketorolac called "15K" was synthesized and found to be substantially more potent than ketorolac for PAK and COX-2 inhibition, and cytotoxicity against lung and melanoma cancer cell lines [127]. In addition, this compound inhibited embryonic angiogenesis in a chorioallantoic membrane assay [128]. These and future experimental studies are critical for resolving key questions on the benefits of specific NSAIDs, including ketorolac or future derivatives, in cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Dual Actions of Ketorolac in Metastatic Ovarian Cancer

Hudson

Cook

Grimes

et al. 2019

Cancers

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Cytoreductive surgery and chemotherapy are cornerstones of ovarian cancer treatment, yet disease recurrence remains a significant clinical issue. Surgery can release cancer cells into the circulation, suppress anti-tumor immunity, and induce inflammatory responses that support the growth of residual disease. Intervention within the peri-operative window is an under-explored opportunity to mitigate these consequences of surgery and influence the course of metastatic disease to improve patient outcomes. One drug associated with improved survival in cancer patients is ketorolac. Ketorolac is a chiral molecule administered as a 1:1 racemic mixture of the S- and R-enantiomers. The S-enantiomer is considered the active component for its FDA indication in pain management with selective activity against cyclooxygenase (COX) enzymes. The R-enantiomer has a previously unrecognized activity as an inhibitor of Rac1 (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42) GTPases. Therefore, ketorolac differs from other non-steroidal anti-inflammatory drugs (NSAIDs) by functioning as two distinct pharmacologic entities due to the independent actions of each enantiomer. In this review, we summarize evidence supporting the benefits of ketorolac administration for ovarian cancer patients. We also discuss how simultaneous inhibition of these two distinct classes of targets, COX enzymes and Rac1/Cdc42, by S-ketorolac and R-ketorolac respectively, could each contribute to anti-cancer activity.

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Section: Discussionmentioning

confidence: 99%

Dual Actions of Ketorolac in Metastatic Ovarian Cancer

Hudson

Cook

Grimes

et al. 2019

Cancers

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“…Furthermore, 15K inhibits the embryonic angiogenesis in ovo (fertilized eggs) with IC 50 around 1 nmol/egg (9).…”

Section: Introductionmentioning

confidence: 99%

1,2,3-Triazolyl ester of ketorolac (15K): Boosting both heat-endurance and lifespan of <i>C. elegans</i> by down-regulating PAK1 at nM levels

Nguyen¹,

Kim

Won

et al. 2018

DD&T

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“…Since YM-155 suppresses the PAK1-dependent expression of COX-2 gene essential for survivin expression [52], there is a possibility that YM-155 might block PAK1 somehow. Recently, we confirmed the anti-PAK1 activity of YM-155 in A549 cancer cell culture (IC 50 around 500 nM), an elixir activity in C. elegans [53], and its anti-angiogenic effect in HUVECs culture (IC 50 around 25 nM) and in ovo (fertilized eggs, IC 50 = 0.5 nmol/egg) as well [54]. YM-155 is currently in clinical trials (phase 2) for a variety of cancers including pancreatic cancer.…”

Section: 23-triazolyl Esters Of Ketorolc (15 K)mentioning

confidence: 52%

Natural or Synthetic Anti-Melanogenic Compounds That Block the PDGFR-EGFR-PAK1-MITF-Tyrosinase Signaling Pathway

Miyata¹,

Pham-Thi²,

Ahn³

2017

J Dermatol Res Ther

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A natural sleeping pill and "elixir" (longevity-promoter) called "Melatonin" is one of the first natural anti-melanogenic compounds, and originally derived from bovine pineal glands. However, currently the majority of melatonin product in the market is chemically synthesized. Since then a wide variety of anti-melanogenic compounds such as curcumin, CAPE (Caffeic Acid Phenethyl Ester), and Artepillin C (ARC) were identified in nature as well as chemically synthesized compounds such as Gleevec. These anti-melanogenic compounds share a series of interesting biological properties such as anti-cancer, anti-inflammatory, anti-ageing (longevity-promoting), immune-boosting, anti-malaria, and anti-diabetic activities. However, the precise molecular mechanism underlying their anti-melanogenic action has remained to be clarified until recently. Finally we found the first clue to understanding of the "melanogenic" signalling pathway involving the major oncogenic/ageing kinase called PAK1 (RAC/CDC42-activated kinase 1) By siRNA-based silencing of PAK1 gene in murine melanoma cell line (B16F10): (i) The major growth hormone in serum called PDGF (Platelet-Derived Growth Factor) is essential for the inducible melanogenesis, but not for the exponential growth per se, and (ii) This cytokine activates its receptor called PDGFR, a Tyr-kinase on the cell surface, and induces another cell surface receptor Tyr-kinase called EGFR (Epidermal Growth Factor Receptor), to form a heterodimer with PDGFR, activating the down-stream melanogenic/oncogenic signalling pathway involving PAK1 and eventually MITF (Microphthalmia-Associated Transcription Factor) essential for expression of Tyrosinase and its Related Protein (TRP) genes. Melatonin and many other anti-melanogenic compounds block PAK1 directly or indirectly, and eventually down-regulate tyrosinase or TRP which is essential for melanin biosynthesis from an amino acid called tyrosine.

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Both triazolyl ester of ketorolac (15K) and YM155 inhibit the embryonic angiogenesis <i>in ovo</i> (fertilized eggs) <i>via</i> their common PAK1-survivin/VEGF signaling pathway

Cited by 7 publications

References 19 publications

Dual Actions of Ketorolac in Metastatic Ovarian Cancer

Dual Actions of Ketorolac in Metastatic Ovarian Cancer

1,2,3-Triazolyl ester of ketorolac (15K): Boosting both heat-endurance and lifespan of <i>C. elegans</i> by down-regulating PAK1 at nM levels

Natural or Synthetic Anti-Melanogenic Compounds That Block the PDGFR-EGFR-PAK1-MITF-Tyrosinase Signaling Pathway

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