title: Anti-breast tumor activity of Eclipta extract in-vitro and in-vivo: novel evidence of endoplasmic reticulum specific localization of Hsp60 during apoptosis.
abstract: Major challenges for current therapeutic strategies against breast cancer are associated with drug-induced toxicities. Considering the immense potential of bioactive phytochemicals to deliver non-toxic, efficient anti-cancer therapeutics, we performed bio-guided fractionation of Eclipta alba extract and discovered that particularly the chloroform fraction of Eclipta alba (CFEA) is selectively inducing cytotoxicity to breast cancer cells over non-tumorigenic breast epithelial cells. Our unbiased mechanistic hunt revealed that CFEA specifically activates the intrinsic apoptotic pathway by disrupting the mitochondrial membrane potential, upregulating Hsp60 and downregulating the expression of anti-apoptotic protein XIAP. By utilizing Hsp60 specific siRNA, we identified a novel pro-apoptotic role of Hsp60 and uncovered that following CFEA treatment, upregulated Hsp60 is localized in the endoplasmic reticulum (ER). To our knowledge, this is the first evidence of ER specific localization of Hsp60 during cancer cell apoptosis. Further, our LC-MS approach identified that luteolin is mainly attributed for its anti-cancer activities. Moreover, oral administration of CFEA not only offers potential anti-breast cancer effects in-vivo but also mitigates tumor induced hepato-renal toxicity. Together, our studies offer novel mechanistic insight into the CFEA mediated inhibition of breast cancer and may potentially open up new avenues for further translational research.
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Arya
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India.
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Singh
authors.affiliation: Toxicology Division, CSIR-CDRI, Lucknow-226031, India.
authors.forename: Navneet K
authors.initials: NK
authors.lastname: Yadav
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-CDRI, Lucknow-226031, India.
authors.forename: Srikanth H
authors.initials: SH
authors.lastname: Cheruvu
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-CDRI, Lucknow-226031, India.
authors.forename: Zakir
authors.initials: Z
authors.lastname: Hossain
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Meena
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India.|Academy of Scientific and Innovative Research, New Delhi, India.
authors.forename: Shrankhla
authors.initials: S
authors.lastname: Maheshwari
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India.
authors.forename: Anup K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India.
authors.forename: Uzma
authors.initials: U
authors.lastname: Shahab
authors.affiliation: Botany Division, CSIR-CDRI, Lucknow-226031, India.
authors.forename: Chetan
authors.initials: C
authors.lastname: Sharma
authors.affiliation: Electron Microscopy Unit, CSIR-CDRI, Lucknow-226031, India.
authors.forename: Kavita
authors.initials: K
authors.lastname: Singh
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-CDRI, Lucknow-226031, India.
authors.forename: Tadigoppula
authors.initials: T
authors.lastname: Narender
authors.affiliation: Electron Microscopy Unit, CSIR-CDRI, Lucknow-226031, India.
authors.forename: Kalyan
authors.initials: K
authors.lastname: Mitra
authors.affiliation: Botany Division, CSIR-CDRI, Lucknow-226031, India.
authors.forename: Kamal R
authors.initials: KR
authors.lastname: Arya
authors.affiliation: Toxicology Division, CSIR-CDRI, Lucknow-226031, India.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Pharmacokinetics and Metabolism Division, CSIR-CDRI, Lucknow-226031, India.
authors.forename: Jiaur R
authors.initials: JR
authors.lastname: Gayen
authors.affiliation: Biochemistry Division, CSIR-Central Drug Research Institute (CDRI), Lucknow-226031, India.|Academy of Scientific and Innovative Research, New Delhi, India.
authors.forename: Dipak
authors.initials: D
authors.lastname: Datta
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018834:Chaperonin 60 / Q000235:genetics / Q000378:metabolism*; D002725:Chloroform / Q000737:chemistry; D036601:Eclipta / Q000737:chemistry*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D008517:Phytotherapy / Q000379:methods; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018834:Chaperonin 60; D010936:Plant Extracts; D051636:X-Linked Inhibitor of Apoptosis Protein; D002725:Chloroform