The Anti-Cancer Effects of Frondoside A

Adrian, Thomas E.; Collin, Peter D.

doi:10.3390/md16020064

Cited by 28 publications

(35 citation statements)

References 59 publications

(205 reference statements)

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“…Many studies have reported that sea cucumber extract contains several compounds, including mono sulfated tritepenoid glycoside Frondoside A, disulfated glycoside Frondoside B, trisulfated glycoside Frondoside C, eicosapentaenoic acid, fucosylated chondroitin sulfate, nobiliside D, 12-methyltetradecanoic acid, sphingoid and canthaxanthin/astaxanthin, that have induced apoptosis in solid cancers, including breast, liver, renal, cervical, lung, and colorectal cancer cells [15,24,25,26]. Amidi et al reported that (Z)-2,3-diphenylacrylonitrile molecules isolated from Persian Gulf SC were identified as potential anti-cancer agents [27].…”

Section: Discussionmentioning

confidence: 99%

Sea Cucumber (Stichopus japonicas) F2 Enhanced TRAIL-Induced Apoptosis via XIAP Ubiquitination and ER Stress in Colorectal Cancer Cells

et al. 2019

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Natural products have shown great promise in sensitizing cells to TNF-related apoptosis-inducing ligand (TRAIL) therapy. Sea cucumber (SC) extracts possess antitumor activity, and hence their potential to sensitize colorectal cancer (CRC) cells to TRAIL therapy was evaluated. This study used Western blotting to evaluate the combination effects of SC and TRAIL in CRC, and determined the molecular mechanism underlying these effects. SC fractions and TRAIL alone did not affect apoptosis; however, combined treatment dramatically induced the apoptosis of CRC cells, but not of normal colon cells. Combined treatment induced the expression of apoptotic proteins (poly (ADP-ribose) polymerase (PARP), caspase 3, and 8), and this effect was markedly inhibited by the ubiquitination of X-linked inhibitor of apoptosis protein (XIAP). SC did not affect the mRNA levels, but it increased proteasomal degradation and ubiquitination of the XIAP protein. Furthermore, SC induced reactive oxygen species (ROS) production, thereby activating c-Jun N-terminal kinase (JNK) and endoplasmic reticulum (ER) stress-related apoptotic pathways in CRC. Altogether, our results demonstrate that the SC F2 fraction may sensitize CRC cells to TRAIL-induced apoptosis through XIAP ubiquitination and ER stress.

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Section: Discussionmentioning

confidence: 99%

Sea Cucumber (Stichopus japonicas) F2 Enhanced TRAIL-Induced Apoptosis via XIAP Ubiquitination and ER Stress in Colorectal Cancer Cells

et al. 2019

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“…The PI3K pathway has been shown to be a dominant signaling pathway in different nucleate cell types, which regulates the balance between apoptosis and survival [34]. Several groups have reported that frondoside A exerts potent anti-cancer effects in vitro and in vivo [19,35]. It is conceivable that this compound also affects the viability of non-malignant cells, such as platelets.…”

Section: Discussionmentioning

confidence: 99%

The Marine-Derived Triterpenoid Frondoside A Inhibits Thrombus Formation

et al. 2020

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Background:The marine-derived triterpenoid frondoside A inhibits the phosphatidylinositol-3-kinase (PI3K) pathway in cancer cells. Because this pathway is also crucially involved in platelet activation, we studied the effect of frondoside A on thrombus formation. Methods: Frondoside A effects on platelet viability, surface adhesion molecule expression, and intracellular signaling were analyzed by flow cytometry and Western blot. The effect of frondoside A was analyzed by photochemically induced thrombus formation in the mouse dorsal skinfold chamber model and by tail vein bleeding. Results: Concentrations of up to 15 µM frondoside A did not affect the viability of platelets, but reduced their surface expression of P-selectin (CD62P) and the activation of glycoprotein (GP)IIb/IIIa after agonist stimulation. Additional mechanistic analyses revealed that this was mediated by downregulation of PI3K-dependent Akt and extracellular-stimuli-responsive kinase (ERK) phosphorylation. Frondoside A significantly prolonged the complete vessel occlusion time in the mouse dorsal skinfold chamber model of photochemically induced thrombus formation and also the tail vein bleeding time when compared to vehicle-treated controls. Conclusion: Our findings demonstrated that frondoside A inhibits agonist-induced CD62P expression and activation of GPIIb/IIIa. Moreover, frondoside A suppresses thrombus formation. Therefore, this marine-derived triterpenoid may serve as a lead compound for the development of novel antithrombotic drugs.

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“…For example, frondoside A (FRA) from a sea cucumber, that directly inhibits PAK1 with IC 50 around 1 µM (17), inhibits the growth of GEMresistant human pancreatic cancer cells (AsPC-1, S2013, MiaPaCa2) in culture with the same IC 50 . Furthermore, frondoside A inhibits the growth of pancreatic cancer xenografts of AsPC-1 and S2013 cells in mice with an IC 50 below 100 µg/kg/day (18). Another natural PAK1blocker called triptolide or its prodrug (phosphorylated derivative) called minnelide inhibited the growth of GEM-resistant human pancreatic cancer xenografts in mice with the IC 50 around 0.3 mg/kg/day (19).…”

Section: Discussionmentioning

confidence: 99%

1,2,3-Triazolyl ester of ketorolac (15K), a potent PAK1 blocker, inhibits both growth and metastasis of orthotopic human pancreatic cancer xenografts in mice

Hennig

Albawardi

Almarzooqi

et al. 2019

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More than 90% of human pancreatic cancers carry the oncogenic mutant of Ki-RAS and their growth depends on its downstream kinase PAK1, mainly because PAK1 blocks the apoptosis of cancer cells selectively. We developed a highly cell-permeable PAK1-blocker called 15K from an old painkiller (ketorolac), that is shown here to inhibit the growth of three pancreatic cancer cell lines with IC 50 values ranging 41-88 nM in vitro. The anti-cancer effect of 15K was further investigated in an orthotopic xenograft model with gemcitabine (GEM)-resistant human pancreatic cancer cell lines (AsPC-1 and BxPC-3) expressing luciferase in athymic mice. During 4 weeks, 15K blocks total burden (growth) of both AsPC-1 and BxPC-3 tumors (measured as radians/sec) with the IC 50 below daily dose of 0.1 mg/kg, i.p. In a similar manner 15K reduced both their invasion and metastases as well, while it had no effect on either body weight or hematological parameters even at 5 mg/kg/day. To the best of our knowledge, 15K is so far the most potent among synthetic PAK1-blockers in vivo, and could be potentially useful for therapy of GEM-resistant cancers.

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The Anti-Cancer Effects of Frondoside A

Cited by 28 publications

References 59 publications

Sea Cucumber (Stichopus japonicas) F2 Enhanced TRAIL-Induced Apoptosis via XIAP Ubiquitination and ER Stress in Colorectal Cancer Cells

Sea Cucumber (Stichopus japonicas) F2 Enhanced TRAIL-Induced Apoptosis via XIAP Ubiquitination and ER Stress in Colorectal Cancer Cells

The Marine-Derived Triterpenoid Frondoside A Inhibits Thrombus Formation

1,2,3-Triazolyl ester of ketorolac (15K), a potent PAK1 blocker, inhibits both growth and metastasis of orthotopic human pancreatic cancer xenografts in mice

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