title: PI3K target based novel cyano derivative of betulinic acid induces its signalling inhibition by down-regulation of pGSK3β and cyclin D1 and potentially checks cancer cell proliferation.
abstract: In spite of the Betulinic acid (BA) being recognized as anticancerous source; its further use in clinical development is greatly hampered because of its poor pharmacokinetic properties. To circumvent these limitations, we synthesized a PI3K target based library of 18 triazole based derivatives and we identified a C-3 cyano analog of betulinic acid (CBA) with significant cell death effects with 5-7 fold higher potency than BA in various cancers. Importantly, no such report is available demonstrating the involvement of BA or its structural analogs in the modulation of PI3K pathway. Using, human leukemia HL-60 cells as a model, we for the first time report that CBA decreased expression of PI3K p110α, p85α, and pAKT in HL-60. Furthermore, we could find significant depletion of pGSK3β, cyclin D1 and increased expression of p21/cip, p27/Kip proteins. CBA induced G0/G1 cell cycle arrest, increased sub-G0 DNA fraction and annexin V binding of the cells besides imparting the typical surface features of cell death. Also, this target specific inhibition was associated with mitochondrial apoptosis as was reflected by expression studies of various proteins together with reactive oxygen species generation and decline in mitochondrial trans membrane potential. The apoptotic effectors i.e., caspase 8 and caspase 9 were found to get upregulated besides PI3K associated DNA repair enzyme i.e., PARP cleavage was observed. Thus, our results elucidated that CBA or other BA based small molecules inhibit PI3K/AKT pathway with induction of subsequent cancer cell death which may be useful therapeutic strategy against leukemias and possibly other cancers.
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road Jammu, India.|Bioorganic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road Jammu, India.
authors.forename: Rabiya
authors.initials: R
authors.lastname: Majeed
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road Jammu, India.
authors.forename: Aashiq
authors.initials: A
authors.lastname: Hussain
authors.affiliation: Bioorganic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road Jammu, India.|CSIR-Academy of Scientific & Innovative Research, Govt. of India, New Delhi, India.
authors.forename: Payare L
authors.initials: PL
authors.lastname: Sangwan
authors.affiliation: Bioorganic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road Jammu, India.
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Chinthakindi
authors.affiliation: Bioorganic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road Jammu, India.
authors.forename: Imran
authors.initials: I
authors.lastname: Khan
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road Jammu, India.
authors.forename: Parduman R
authors.initials: PR
authors.lastname: Sharma
authors.affiliation: Bioorganic Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road Jammu, India.
authors.forename: Surrinder
authors.initials: S
authors.lastname: Koul
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road Jammu, India.
authors.forename: Ajit K
authors.initials: AK
authors.lastname: Saxena
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road Jammu, India.|CSIR-Academy of Scientific & Innovative Research, Govt. of India, New Delhi, India.
authors.forename: Abid
authors.initials: A
authors.lastname: Hamid
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism*; D015536:Down-Regulation; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018922:HL-60 Cells; D006801:Humans; D061986:MCF-7 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D053978:Pentacyclic Triterpenes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D014315:Triterpenes / Q000819:agonists* / Q000494:pharmacology; D000094062:Betulinic Acid
chemical_list: C530104:CCND1 protein, human; D053978:Pentacyclic Triterpenes; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014230:Triazoles; D014315:Triterpenes; D019938:Cyclin D1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D000094062:Betulinic Acid
keywords: GSK3β; apoptosis; betulinic acid; leukemia; metabolism; phosphotidylinositol-3 kinase