title: Antiproliferative potential of a novel parthenin analog P16 as evident by apoptosis accompanied by down-regulation of PI3K/AKT and ERK pathways in human acute lymphoblastic leukemia MOLT-4 cells.
abstract: Leukemia is one of the deadliest types of cancer. Lack of effective treatment strategies has resulted in an extensive quest for new therapeutic molecules against it. This study explores the molecular mechanism of anticancer activity of P16, a semisynthetic analog of parthenin, against the human acute lymphoblastic leukemia MOLT-4 cells. P16 displayed antiproliferative activity in different cancer cell lines; however, MOLT-4 cells showed highest sensitivity for P16 with IC50 value of 0.6μM. Further studies revealed that P16 induced cell death by apoptosis. It caused mitochondrial stress, which was mediated by the translocation of Bax from cytosol to mitochondria and release of cytochrome c into the cytosol and consequent activation of caspase-9. However, P16 was also able to activate caspase-8, thus involving both extrinsic and intrinsic pathways of apoptosis. Further, activation of caspase-3 led to cleavage of its target proteins PARP-1 and ICAD, which resulted in apoptotic DNA damage. P16 induced apoptosis was accompanied by the down-regulation of important leukemic cell survival proteins like pAKT (S473), pAKT (T308), pP70S6K, pCRAF, and pERK1/2. However, inhibition of caspases by Z-VAD-FMK reversed the down-regulatory effect of P16 on pAKT (S473) and pP70S6K, as evident by the cell viability assay and flow cytometric analysis but this inhibition did not completely reverse the antiproliferative effect of P16, thereby indicating the role of additional factors apart from caspases in P16 induced apoptosis in MOLT-4 cells. Owing to its antiproliferative potential against leukemia cells, P16 can further be explored as an effective therapeutics against leukemia.
authors.affiliation: Department of Biotechnology, Panjab University, Chandigarh 160014, India.
authors.forename: Akshra
authors.initials: A
authors.lastname: Goswami
authors.affiliation: Division of Natural Products Microbes, Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Bhahwal Ali
authors.initials: BA
authors.lastname: Shah
authors.affiliation: Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Ajay
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, University of Kashmir, Srinagar 190006, J&K, India.
authors.forename: Masood Ahmad
authors.initials: MA
authors.lastname: Rizvi
authors.affiliation: Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Suresh
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Shashi
authors.initials: S
authors.lastname: Bhushan
authors.affiliation: Division of Cancer Pharmacology, Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Fayaz Ahmed
authors.initials: FA
authors.lastname: Malik
authors.affiliation: Department of Biotechnology, Goswami Ganesh Dutt Sanatan Dharam College, Sector-32, Chandigarh 160047, India.
authors.forename: Navneet
authors.initials: N
authors.lastname: Batra
authors.affiliation: Department of Biotechnology, Sri Guru Gobind Singh College, Sector-26, Chandigarh 160019, India. Electronic address: amit.molbio@gmail.com.
authors.forename: Amit
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Department of Biotechnology, Panjab University, Chandigarh 160014, India. Electronic address: jagtar72@gmail.com.
authors.forename: Jagtar
authors.initials: J
authors.lastname: Singh
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; D006576:Heterocyclic Compounds, 4 or More Rings; D012717:Sesquiterpenes; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; C022097:parthenin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases
keywords: Apoptosis; ERK pathway; MOLT-4; PI3K/AKT pathway; Parthenin analog (P16); Z-VAD-FMK