title: PAC, a novel curcumin analogue, has anti-breast cancer properties with higher efficiency on ER-negative cells.
abstract: We have investigated here the anti-breast cancer properties of two novel curcumin analogues, EAC and PAC. Apoptosis was assessed by the annexin V/propidium iodide (PI) assay on different breast cancer and normal cells. Immunoblotting analysis determined the effects of these agents on different apoptotic and oncogenic proteins. Furthermore, flow cytometry and Elispot were utilised to investigate the effects on the cell cycle and the production of cytokines, respectively. Breast cancer tumour xenografts were developed in nude mice. Finally, (18)F-radiolabeled PAC and curcumin were produced to study their bioavailability and tissue biodistribution in mice. PAC is five times more efficient than curcumin and EAC in inducing apoptosis, mainly via the internal mitochondrial route. This effect was 10-fold higher against ER-negative as compared to ER-positive cells, and ectopic expression of ERα rendered ER-negative breast cancer cells more resistant to PAC. In addition, PAC delayed the cell cycle at G2/M phase with a stronger effect on ER-negative cells. Moreover, PAC exhibited strong capacity as an immuno-inducer through reducing the secretion of the two major Th2 cytokines IL-4 and IL-10. Importantly, PAC significantly reduced tumour size, and triggered apoptosis in vivo. Furthermore, PAC inhibited survivin, NF-kB and its downstream effectors cyclin D1 and Bcl-2, and strongly up-regulated p21(WAF1) both in vitro and in tumours. Besides, PAC exhibited higher stability in blood and greater biodistribution and bioavailability than curcumin in mice. These results indicate that PAC could constitute a powerful, yet not toxic, new chemotherapeutic agent against ER-negative breast tumours.
authors.affiliation: Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, KSA.
authors.forename: Ensaf M
authors.initials: EM
authors.lastname: Al-Hujaily
authors.forename: Ameera Gaafar
authors.initials: AG
authors.lastname: Mohamed
authors.forename: Ibtehaj
authors.initials: I
authors.lastname: Al-Sharif
authors.forename: Khairia M
authors.initials: KM
authors.lastname: Youssef
authors.forename: Pulicat S
authors.initials: PS
authors.lastname: Manogaran
authors.forename: Basem
authors.initials: B
authors.lastname: Al-Otaibi
authors.forename: Amal
authors.initials: A
authors.lastname: Al-Haza'a
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Al-Jammaz
authors.forename: Khaled
authors.initials: K
authors.lastname: Al-Hussein
authors.forename: Abdelilah
authors.initials: A
authors.lastname: Aboussekhra
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001597:Benzylidene Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001923:Brain Chemistry; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D052138:Genes, Neoplasm; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000037:antagonists & inhibitors; D015847:Interleukin-4 / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D010881:Piperidones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: C568297:5-bis(4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperidone; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001597:Benzylidene Compounds; D050759:Cyclin-Dependent Kinase Inhibitor p21; C508609:IL10 protein, human; C508598:IL4 protein, human; D010881:Piperidones; D011960:Receptors, Estrogen; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma