title: Nanoquinacrine induced apoptosis in cervical cancer stem cells through the inhibition of hedgehog-GLI1 cascade: Role of GLI-1.
abstract: To improve the pharmacokinetics and to study the anti-cervical cancer and anti-stem cells (CSCs) mechanism of Quinacrine (QC), a spherical nano particle of QC (i.e. NQC) was prepared and characterized. QC and NQC showed higher cytotoxicity in multiple cancer cells than the normal epithelial cells. NQC exhibited more toxicity in cervical cancer cells and its CSCs than QC. A dose-dependent decreased expression of Hedgehog-GLI (HH-GLI) components were noted in NQC treated HeLa cells and its CSCs. NQC increased the expressions of negatively regulated HH-GLI components (GSK3β, PTEN) and caused apoptosis in CSCs. Reduction of GLI1 at mRNA and promoter level were noted after NQC exposure. The expressions of HH-GLI components, GLI1 promoter activity and apoptosis were unaltered in NQC treated GLI1-knockdown cells. In silico, cell based and in vitro reconstitution assay revealed that NQC inhibit HH-GLI cascade by binding to the consensus sequence (5'GACCACCCA3') of GLI1 in GLI-DNA complex through destabilizing DNA-GLI1 complex. NQC reduced the tumors size and proliferation marker Ki-67 in an in vivo xenograft mice model. Thus, NQC induced apoptosis in cancers through inhibition of HH-GLI cascade by GLI1. Detail interaction of QC-DNA-GLI complex can pave path for anticancer drug design.
authors: Cancer Biology Division, KIIT School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Orissa, 751024, India.
authors: Anmada
authors: A
authors: Nayak
authors: Cancer Biology Division, KIIT School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Orissa, 751024, India.
authors: Shakti Ranjan
authors: SR
authors: Satapathy
authors: Cancer Biology Division, KIIT School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Orissa, 751024, India.
authors: Dipon
authors: D
authors: Das
authors: Cancer Biology Division, KIIT School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Orissa, 751024, India.
authors: Sumit
authors: S
authors: Siddharth
authors: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab 160062, India.
authors: Neha
authors: N
authors: Tripathi
authors: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab 160062, India.|Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab 160062, India.
authors: Prasad V
authors: PV
authors: Bharatam
authors: Cancer Biology Division, KIIT School of Biotechnology, KIIT University, Campus-11, Patia, Bhubaneswar, Orissa, 751024, India.
authors: ChanakyaNath
authors: C
authors: Kundu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D053768:Metal Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011796:Quinacrine / Q000008:administration & dosage* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000071676:Zinc Finger Protein GLI1 / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D000071676:Zinc Finger Protein GLI1; D011796:Quinacrine