Effect of conjugates of all-trans-retinoic acid and shorter polyene chain analogues with amino acids on prostate cancer cell growth.
In the present work, a series of conjugates of amino acids with all-trans-retinoic acid (ATRA) and shorter polyene chain analogues were rationally designed, synthesized by coupling the succinimidyl active esters of the acidic retinoids with appropriately protected amino acids or peptides followed by deprotection, and examined for their possible effect on viability of human prostate cancer LNCaP cells. In contrast to ATRA, all conjugates bearing amino acids with polar side chains showed no inhibitory effect on LNCaP cell proliferation, while conjugates with alpha-amino acids with lipophilic side chain, such as 7, or linear amino acids, such as 9, significantly decreased prostate cancer LNCaP cell number. Interestingly, while the effect of ATRA was RARalpha-dependent, the effect of its active analogues was not inhibited by a selective RARalpha antagonist. Cell cycle analysis showed no effect on cell cycle, while quantitative analysis by annexin V-propidium iodide staining revealed that neither ATRA nor its analogues affected LNCaP cell apoptosis or necrosis. These results demonstrate that compounds 7 and 9 are potentially useful agents that warrant further preclinical development for treatment of prostate cancer.
Department of Pharmacy, Laboratory of Molecular Pharmacology, School of Health Sciences, University of Patras, University Campus, Patras, Greece.
Eldem
E
Sadikoglou
George
G
Magoulas
Christina
C
Theodoropoulou
Constantinos M
CM
Athanassopoulos
Efstathia
E
Giannopoulou
Olga
O
Theodorakopoulou
Denis
D
Drainas
Dionysios
D
Papaioannou
Evangelia
E
Papadimitriou
D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D011090:Polyenes / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000473:pathology*; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors; D000072482:Retinoic Acid Receptor alpha; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014212:Tretinoin / Q000737:chemistry* / Q000494:pharmacology*
D000596:Amino Acids; D000970:Antineoplastic Agents; D011090:Polyenes; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin