A Bromophosphonate Analogue of Lysophosphatidic Acid Surpasses Dacarbazine in Reducing Cell Proliferation and Viability of MeWo Melanoma Cells

Nguyen, Duy T.; Nguyen, Oanh; Zhang, Honglu; Prestwich, Glenn D.; Murph, Mandi M.

doi:10.5772/18702

Cited by 2 publications

(4 citation statements)

References 21 publications

(14 reference statements)

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“…Thus, we compared these single agents against both the anti-BrP-LPA and the mixed diastereomers BrP-LPA on the viability of MeWo melanoma cells. Indeed, both BrP-LPA compounds were more effective single-agents at 10 µM and 100 µM than either dacarbazine or temozolomide, at concentration ranging from 10-1000 µM [59]. This suggests that targeted approaches against ATX in melanoma have potential and further results will be reported in due time.…”

Section: Atx In Melanomamentioning

confidence: 91%

“…BrP-LPA is also a pan-antagonist of LPA 1-3, which is effective in decreasing to tumor growth in orthotopic xenograft models of breast cancer using MDA-MB-231 cells [50] and in metastasis of A549 lung cancer cells in nude mice [51]. We have also previously demonstrated that BrP-LPA is more effective than dacarbazine in reducing the viability of melanoma cells [59].…”

Section: Compound Classmentioning

confidence: 94%

“…Although accumulating studies suggest that inhibiting ATX activity could provide a novel adjuvant therapy for improving the efficacy of existing chemotherapeutic agents, we have previously demonstrated a role for ATX inhibitors as monotherapy against advanced cutaneous melanoma [2,48,59]. After injecting B16F10 metastatic melanoma cells into the tail veins of C57/Bl6 mice, we observed a significant reduction in the number of lung nodules, which represent metastatic melanoma tumors, after treatment with a phosphonothionate analogue of carba cyclic phosphatidic acid, thio-ccPA 18:1 [2].…”

Section: Atx In Melanomamentioning

confidence: 99%

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Autotaxin – An Enzymatic Augmenter of Malignant Progression Linked to Inflammation

Brindley¹,

Benesch²,

Murph³

2015

Melanoma - Current Clinical Management and Future Therapeutics

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Malignant melanoma cells are incredibly hardy, stemming from their intrinsic defensive nature. These cells inherit unique characteristics, which allowed their non-malignant predecessors, melanocytes, to survive solar ultraviolet radiation and simultaneously provide protection to neighboring cells. Most other cell types would die after such harsh exposure. Unsurprisingly, melanoma cells, which survive ultraviolet radiation, are intrinsically resistant to most chemotherapy. Although there are numerous molecular reasons for this reality, herein we focus on the causal role of autotaxin (ATX) in melanoma. ATX is a 125 kDa glycoprotein enzyme that was initially discovered in the serum-free medium of A2058 human melanoma cells by Stracke et al. in 1992 [1] (Figure 1). Today, we know much more about this glycoprotein enzyme and how it affects melanoma. Indeed, ATX is highly overexpressed among primary melanomas and metastatic melanomas, in comparison to melanoma in situ and in normal skin [2]. In fact, "autotaxin" derived its name based on its initial property as an "autocrine motility factor". The rationale is that A2058 melanoma cells secrete ATX into culture medium and then respond to it with self-stimulated random and directed motility. Even though the amount of ATX in conditioned medium is less than 0.005% of total protein, only miniscule amounts, detected in picomolar and nanomolar concentrations, are needed to promote motility. [1] This suggests a large role for a low-abundant secreted enzyme. There are five alternatively-spliced isoforms of ATX that are catalytically active [3,4]. The original ATX protein described in 1992 is termed ATXα, whereas the most abundant isoform is ATXβ and is the same isoform responsible for plasma lysoPLD activity [5]. Full length ATX

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Section: Atx In Melanomamentioning

confidence: 91%

Section: Compound Classmentioning

confidence: 94%

Section: Atx In Melanomamentioning

confidence: 99%

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Autotaxin – An Enzymatic Augmenter of Malignant Progression Linked to Inflammation

Brindley¹,

Benesch²,

Murph³

2015

Melanoma - Current Clinical Management and Future Therapeutics

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“…We previously synthesized ATX inhibitors and examined their biological activity against melanoma 8a, 8b, 23 and other malignancies 15d, 15e, 24 . Since the in vitro activity observed by ATX inhibitors on melanoma cells is striking, we hypothesized that the mechanism of action is a directly-targeted, cellular consequence.…”

Section: Introductionmentioning

confidence: 99%

Vinyl sulfone analogs of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma

Murph

Jiang

Altman

et al. 2015

Bioorganic & Medicinal Chemistry

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Autotaxin (ATX) is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. This unique ectonucleotide pyrophosphatase and phosphodiesterase facilitates the removal of a choline headgroup from lysophosphatidylcholine (LPC) to yield lysophosphatidic acid (LPA), which is a potent lipid stimulator of tumorigenesis. Thus, ATX has received renewed attention because it has a prominent role in malignant progression with significant translational potential. Specifically, we sought to develop active site-targeted irreversible inhibitors as anti-cancer agents. Herein we describe the synthesis and biological activity of an LPC-mimetic electrophilic affinity label that targets the active site of ATX, which has a critical threonine residue that acts as a nucleophile in the lysophospholipase D reaction to liberate choline. We synthesized a set of quaternary ammonium derivative-containing vinyl sulfone analogs of LPC that function as irreversible inhibitors of ATX and inactivate the enzyme. The analogs were tested in cell viability assays using multiple cancer cell lines. The IC50 values ranged from 6.74 – 0.39 μM, consistent with a Ki of 3.50 μM for inhibition of ATX by the C16H33 vinyl sulfone analog CVS-16 (10b). A phenyl vinyl sulfone control compound, PVS-16, lacking the choline-like quaternary ammonium mimicking head group moiety, had little effect on cell viability and did not inhibit ATX. Most importantly, CVS-16 (10b) significantly inhibited melanoma progression in an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that CVS-16 (10b) is a potent and irreversible ATX inhibitor with significant biological activity both in vitro and in vivo.

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A Bromophosphonate Analogue of Lysophosphatidic Acid Surpasses Dacarbazine in Reducing Cell Proliferation and Viability of MeWo Melanoma Cells

Cited by 2 publications

References 21 publications

Autotaxin – An Enzymatic Augmenter of Malignant Progression Linked to Inflammation

Autotaxin – An Enzymatic Augmenter of Malignant Progression Linked to Inflammation

Vinyl sulfone analogs of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma

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