Inhibition of phosphotidylinositol-3 kinase pathway by a novel naphthol derivative of betulinic acid induces cell cycle arrest and apoptosis in cancer cells of different origin

• Published in: Cell death & disease Vol. 5; no. 10; p. e1459
• Main Authors: Majeed, R, Hamid, A, Sangwan, P L, Chinthakindi, P K, Koul, S, Rayees, S, Singh, G, Mondhe, D M, Mintoo, M J, Singh, S K, Rath, S K, Saxena, A K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2014; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/67/1059/99; 631/80/82/23; 631/92/349; Animals; Antibodies; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Enzyme Inhibitors - pharmacology; Female; Humans; Immunology; Life Sciences; Molecular Structure; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; Original; original-article; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Triterpenes - chemistry; Triterpenes - pharmacology
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.387

Betulinic acid (BA) is a pentacyclic triterpenoid natural product reported to inhibit cell growth in a variety of cancers. However, the further clinical development of BA got hampered because of poor solubility and pharmacological properties. Interestingly, this molecule offer several hotspots for structural modifications in order to address its associated issues. In our endeavor, we selected C-3 position for the desirable chemical modification in order to improve its cytotoxic and pharmacological potential and prepared a library of different triazoline derivatives of BA. Among them, we previously reported the identification of a potential molecule, that is, 3{1 N (5-hydroxy-naphth-1yl)-1 H -1,2,3-triazol-4yl}methyloxy betulinic acid (HBA) with significant inhibition of cancer cell growth and their properties. In the present study, we have shown for the first time that HBA decreased the expression of phosphotidylinositol-3 kinase (PI3K) p110 α and p85 α and caused significant downregulation of pAKT and of NF κ B using human leukemia and breast cancer cells as in vitro models. Further it was revealed that PI3K inhibition by HBA induced cell cycle arrest via effects on different cell cycle regulatory proteins that include CDKis cyclins and pGSK3 β . Also, this target-specific inhibition was associated with mitochondrial apoptosis as was reflected by the increased expression of mitochondrial bax, downregulated bcl2 and decreased mitochondrial levels of cytochrome c , together with reactive oxygen species generation and decline in mitochondrial membrane potential. The apoptotic effectors such as caspase 8, caspase 9 and caspase 3 were found to be upregulated besides DNA repair-associated enzyme, that is, PARP cleavage caused cancer cell death. Pharmacodynamic evaluation revealed that both HBA and BA were safe upto the dose of 2000 mg/kg body weight and with acceptable pharmacodynamic parameters. The in vitro data corroborated with in vivo anticancer activity wherein Ehrlich solid tumor showed that HBA as a more potent agent than BA without any body weight loss and mortality.