Homospisulosine induced apoptosis in cervical carcinoma cells is associated with phosphorylation of Bcl-2 and up-regulation of p27/Kip1.
Apoptosis
Cancer
Ceramide
Homospisulosine
Marine
Sphingoid bases
Sphingosine-1-phosphate
Spisulosine
Journal
Journal of applied biomedicine
ISSN: 1214-0287
Titre abrégé: J Appl Biomed
Pays: Poland
ID NLM: 101221755
Informations de publication
Date de publication:
Dec 2023
Dec 2023
Historique:
received:
11
05
2023
accepted:
28
11
2023
medline:
19
12
2023
pubmed:
19
12
2023
entrez:
19
12
2023
Statut:
ppublish
Résumé
Spisulosine (1-deoxysphinganine) is a sphingoid amino alcohol isolated from the sea clams that showed potent antiproliferative activity against a broad spectrum of solid tumors but failed in clinical trials due to neurotoxicity. However, its structural similarity to other bioactive sphingoids, interesting mode of action, and appreciable potency against cancer cells make it a suitable lead for future anticancer drug development. The present study was conducted to elucidate mechanisms of the antiproliferative/cytotoxic effects of newly synthesized spisulosine analog homospisulosine (KP7). The evaluation was performed on cervical carcinoma cells, representing an in vitro model of one of the most common cancer types and a significant worldwide cause of women's cancer mortality. Treatment with homospisulosine (2.0 μM) for 24, 48, and 72 h significantly inhibited the growth of HeLa cells in vitro and induced apoptosis detectable by DNA fragmentation, externalization of phosphatidylserine, dissipation of mitochondrial membrane potential, activation of caspase-3 and cleavage of PARP. In addition, treating HeLa cells with spisulosine increased p27 and Bcl-2 on protein levels and phosphorylation of Bcl-2 on Ser70 residue. These results support the potential for spisulosine analogs represented here by homospisulosine for future therapeutic development.
Identifiants
pubmed: 38112461
doi: 10.32725/jab.2023.019
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
218-227Subventions
Organisme : Slovak Grant Agency for Science VEGA No
ID : 1/0278/23
Pays : Slovakia
Organisme : Slovak Grant Agency for Science VEGA No
ID : 1/0539/21
Pays : Slovakia
Organisme : Slovak Grant Agency for Science VEGA No
ID : 1/0653/19
Pays : Slovakia
Organisme : Operational Programme Integrated Infrastructure
ID : ITMS2014
Pays : Slovakia
Organisme : Operational Programme Integrated Infrastructure
ID : 313011V455
Pays : Slovakia
Déclaration de conflit d'intérêts
The authors report no conflicts of interest in this work.
Références
Abbas T, Dutta A (2009). p21 in cancer: intricate networks and multiple activities. Nat Rev Cancer 9(6): 400-414. DOI: 10.1038/nrc2657.
pubmed: 19440234
doi: 10.1038/nrc2657
Abukhdeir AM, Park BH (2008). P21 and p27: roles in carcinogenesis and drug resistance. Expert Rev Mol Med 10: e19. DOI: 10.1017/S1462399408000744.
pubmed: 18590585
doi: 10.1017/S1462399408000744
Baird RD, Kitzen J, Clarke PA, Planting A, Reade S, Reid A, et al. (2009). Phase I safety, pharmacokinetic, and pharmacogenomic trial of ES-285, a novel marine cytotoxic agent, administered to adult patients with advanced solid tumors. Mol Cancer Ther 8(6): 1430-1437. DOI: 10.1158/1535-7163.MCT-08-1167.
pubmed: 19509256
doi: 10.1158/1535-7163.MCT-08-1167
Blagosklonny MV (2002). Are p27 and p21 cytoplasmic oncoproteins? Cell Cycle 1(6): 391-393. DOI: 10.4161/cc.1.6.262.
pubmed: 12548011
doi: 10.4161/cc.1.6.262
Burmeister CA, Khan SF, Schafer G, Mbatani N, Adams T, Moodley J, Prince S (2022). Cervical cancer therapies: Current challenges and future perspectives. Tumour Virus Res 13: 200238. DOI: 10.1016/j.tvr.2022.200238.
pubmed: 35460940
doi: 10.1016/j.tvr.2022.200238
Chakraborty C, Hsu CH, Wen ZH, Lin CS (2009). Anticancer drugs discovery and development from marine organism. Curr Top Med Chem 9(16): 1536-1545. DOI: 10.2174/156802609789909803.
pubmed: 19903164
doi: 10.2174/156802609789909803
Cuadros R, Montejo de Garcini E, Wandosell F, Faircloth G, Fernandez-Sousa JM, Avila J (2000). The marine compound spisulosine, an inhibitor of cell proliferation, promotes the disassembly of actin stress fibers. Cancer Lett 152(1): 23-29. DOI: 10.1016/s0304-3835(99)00428-0.
pubmed: 10754202
doi: 10.1016/s0304-3835(99)00428-0
Den Brok MW, Nuijen B, Garcia JL, Miranda E, Calvo P, Manada C, Beijnen JH (2006). Compatibility and stability of the novel anticancer agent ES-285 x HCl formulated with 2-hydroxypropyl-beta-cyclodextrin in infusion devices. Pharmazie 61(1): 21-24.
Den Brok MW, Nuijen B, Meijer DM, Millan E, Manada C, Beijnen JH (2005). Pharmaceutical development of a parenteral lyophilised formulation of the investigational anticancer agent ES-285.HCl. PDA J Pharm Sci Technol 59(4): 246-257.
Haefner B (2003). Drugs from the deep: marine natural products as drug candidates. Drug Discov Today 8(12): 536-544. DOI: 10.1016/s1359-6446(03)02713-2.
pubmed: 12821301
doi: 10.1016/s1359-6446(03)02713-2
Haldar S, Chintapalli J, Croce CM (1996). Taxol induces bcl-2 phosphorylation and death of prostate cancer cells. Cancer Res 56(6): 1253-1255.
Ito T, Deng X, Carr B, May WS (1997). Bcl-2 phosphorylation required for anti-apoptosis function. J Biol Chem 272(18): 11671-11673. DOI: 10.1074/jbc.272.18.11671.
pubmed: 9115213
doi: 10.1074/jbc.272.18.11671
Jimeno J, López-Martín JA, Ruiz-Casado A, Izquierdo MA, Scheuer PJ, Rinehart K (2004). Progress in the clinical development of new marine-derived anticancer compounds. Anticancer Drugs 15(4): 321-329. DOI: 10.1097/00001813-200404000-00003.
pubmed: 15057135
doi: 10.1097/00001813-200404000-00003
Katanyoo K, Sanguanrungsirikul S, Manusirivithaya S (2012). Comparison of treatment outcomes between squamous cell carcinoma and adenocarcinoma in locally advanced cervical cancer. Gynecol Oncol 125(2): 292-296. DOI: 10.1016/j.ygyno.2012.01.034.
pubmed: 22293041
doi: 10.1016/j.ygyno.2012.01.034
Kim SW, Kim HJ, Chun YJ, Kim MY (2010). Ceramide produces apoptosis through induction of p27(kip1) by protein phosphatase 2A-dependent Akt dephosphorylation in PC-3 prostate cancer cells. J Toxicol Environ Health A 73(21-22): 1465-1476. DOI: 10.1080/15287394.2010.511553.
pubmed: 20954073
doi: 10.1080/15287394.2010.511553
Lefever S, Vandesompele J, Speleman F, Pattyn F (2009). RTPrimerDB: the portal for real-time PCR primers and probes. Nucleic Acids Res 37(Database issue): D942-945. DOI: 10.1093/nar/gkn777.
pubmed: 18948285
doi: 10.1093/nar/gkn777
Leibiger C, Kosyakova N, Mkrtchyan H, Glei M, Trifonov V, Liehr T (2013). First molecular cytogenetic high resolution characterization of the NIH 3T3 cell line by murine multicolor banding. J Histochem Cytochem 61(4): 306-312. DOI: 10.1369/0022155413476868.
pubmed: 23321776
doi: 10.1369/0022155413476868
Malve H (2016). Exploring the ocean for new drug developments: Marine pharmacology. J Pharm Bioallied Sci 8(2): 83-91. DOI: 10.4103/0975-7406.171700.
pubmed: 27134458
doi: 10.4103/0975-7406.171700
Mosmann T (1983). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1-2): 55-63. DOI: 10.1016/0022-1759(83)90303-4.
pubmed: 6606682
doi: 10.1016/0022-1759(83)90303-4
National Library of Medicine. National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 9925886, Spisulosine. [online] [cit. 2023-01-22]. Available from: https://pubchem.ncbi.nlm.nih.gov/compound/Spisulosine
Ogretmen B (2018). Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer 18(1): 33-50. DOI: 10.1038/nrc.2017.96.
pubmed: 29147025
doi: 10.1038/nrc.2017.96
Rinehart KL, Fregeau NL, Warwick RA (2000). Spisulosine compounds. Google Patents. [online] [cit. 2023-01-22]. Available from: https://patents.google.com/patent/US20040147615A1/en
Rios Ade O, Antunes LMG, Bianchi, MdLP (2009). Bixin and lycopene modulation of free radical generation induced by cisplatin-DNA interaction. Food Chem 113(4): 1113-1118. DOI: 10.1016/j.foodchem.2008.08.084.
doi: 10.1016/j.foodchem.2008.08.084
Roginsky AB, Ujiki MB, Ding XZ, Adrian TE (2005). On the potential use of flavonoids in the treatment and prevention of pancreatic cancer. In Vivo 19(1): 61-67.
Salcedo M, Cuevas C, Alonso JL, Otero G, Faircloth G, Fernandez-Sousa JM, et al. (2007). The marine sphingolipid-derived compound ES 285 triggers an atypical cell death pathway. Apoptosis 12(2): 395-409. DOI: 10.1007/s10495-006-0573-z.
pubmed: 17191124
doi: 10.1007/s10495-006-0573-z
Sánchez AM, Malagarie-Cazenave S, Olea N, Vara D, Cuevas C, Díaz-Laviada I (2008). Spisulosine (ES-285) induces prostate tumor PC-3 and LNCaP cell death by de novo synthesis of ceramide and PKCzeta activation. Eur J Pharmacol 584(2-3): 237-245. DOI: 10.1016/j.ejphar.2008.02.011.
pubmed: 18343365
doi: 10.1016/j.ejphar.2008.02.011
Schöffski P, Dumez H, Ruijter R, Miguel-Lillo B, Soto-Matos A, Alfaro V, Giaccone G (2011). Spisulosine (ES-285) given as a weekly three-hour intravenous infusion: results of a phase I dose-escalating study in patients with advanced solid malignancies. Cancer Chemother Pharmacol 68(6): 1397-1403. DOI: 10.1007/s00280-011-1612-1.
pubmed: 21465314
doi: 10.1007/s00280-011-1612-1
Singh R, Sharma M, Joshi P, Rawat DS (2008). Clinical status of anti-cancer agents derived from marine sources. Anticancer Agents Med Chem 8(6): 603-617.
doi: 10.2174/187152008785133074
Sithranga Boopathy N, Kathiresan K (2010). Anticancer drugs from marine flora: an overview. J Oncol 2010: 214186. DOI: 10.1155/2010/214186.
pubmed: 21461373
doi: 10.1155/2010/214186
Stanková K, Martinková M, Gonda J, Bago M, Pilátová M, Gönciová G (2015). The convergent total synthesis of cytotoxic homospisulosine and its 3-epi-analogue. Tetrahedron: Asymmetry 26(24): 1394-1407. DOI: 10.1016/j.tetasy.2015.11.001.
doi: 10.1016/j.tetasy.2015.11.001
Vilar E, Grünwald V, Schöffski P, Singer H, Salazar R, Iglesias JL, et al. (2012). A phase I dose-escalating study of ES-285, a marine sphingolipid-derived compound, with repeat dose administration in patients with advanced solid tumors. Invest New Drugs 30(1): 299-305. DOI: 10.1007/s10637-010-9529-9.
pubmed: 20820909
doi: 10.1007/s10637-010-9529-9
Yang W, Soares J, Greninger P, Edelman EJ, Lightfoot H, Forbes S, et al. (2013). Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res 41(Database issue): D955-961. DOI: 10.1093/nar/gks1111.
pubmed: 23180760
doi: 10.1093/nar/gks1111
Zamzami N, Marchetti P, Castedo M, Hirsch T, Susin SA, Masse B, Kroemer G (1996). Inhibitors of permeability transition interfere with the disruption of the mitochondrial transmembrane potential during apoptosis. FEBS Lett 384(1): 53-57. DOI: 10.1016/0014-5793(96)00280-3.
pubmed: 8797802
doi: 10.1016/0014-5793(96)00280-3