Lipophilization of somatostatin analog RC-160 with long chain fatty acid improves its anti-proliferative activity on human oral carcinoma cells in vitro.
Oral cancer which comprises about 40% of total cancers in India, has one of the lowest relative survival rates of all cancers. Epidermal growth factor (EGF) has been known to play a role in the proliferation/malignant transformation of oral neoplasms. Since, the somatostatin analog RC-160 is reported to be a potent inhibitor of EGF stimulated cell proliferation, its anti-proliferative activity in the human oral carcinoma cell line KB was investigated, in this study. RC-160 was found to potently inhibit EGF-induced proliferation in KB cells in vitro, suggesting a therapeutic potential of the same in oral carcinoma. However, the therapeutic potential of RC-160 is limited by its short serum half life. To overcome this limitation, fatty acids namely butanoic acid and myristic acid individually were coupled to RC-160. The lipophilized derivatives of RC-160 were synthesized, purified and characterized. The anti-proliferative activity of lipophilized derivatives of RC-160 on KB cells was evaluated in vitro. Myristoyl-RC-160 (0.75 nM) inhibited the growth of KB cells at a 10-fold lower concentration relative to RC-160 (8.8 nM) and at a 100-fold lower concentration relative to butanoyl-RC-160 (0.83 microM) (p<0.001). The affinity of RC-160 towards somatostatin receptors remains unaltered by lipophilization. The signaling pathways underlying the antineoplastic activity of these lipopeptides are similar to RC-160, and do not involve the stimulation of a protein tyrosine phosphatase or a serine threonine phosphatase 1A and 2A. The anti-proliferative activity of the lipopeptides was found to be mediated by somatostatin receptors and correlates with the inhibition of protein tyrosine kinase activity and decrease in intracellular cAMP levels. Myristoyl-RC-160 displayed significantly greater resistance towards trypsin and serum degradation than RC-160 (p<0.01). These findings demonstrate that RC-160 can inhibit the growth of oral cancer cells in vitro. Lipophilization of RC-160 with long chain fatty acids like myristic acid improves its stability and anti-proliferative activity, in human oral carcinoma cells in vitro, thereby enhancing the scope of improving its therapeutic index.
Dasgupta
P
P
Neuroimmunology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
Singh
A T
AT
Mukherjee
R
R
D018931:Antineoplastic Agents, Hormonal / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020148:Butyric Acid / Q000737:chemistry; D002455:Cell Division / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D005227:Fatty Acids / Q000737:chemistry*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007624:KB Cells; D009062:Mouth Neoplasms / Q000473:pathology*; D019814:Myristic Acid / Q000737:chemistry; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D017481:Receptors, Somatostatin / Q000187:drug effects / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D014357:Trypsin / Q000737:chemistry
D018931:Antineoplastic Agents, Hormonal; D005227:Fatty Acids; D017481:Receptors, Somatostatin; D019814:Myristic Acid; D020148:Butyric Acid; C051458:vapreotide; D013004:Somatostatin; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D014357:Trypsin; D019204:GTP-Binding Proteins