title: Dimethoxycurcumin, a metabolically stable analogue of curcumin enhances the radiosensitivity of cancer cells: Possible involvement of ROS and thioredoxin reductase.
abstract: Dimethoxycurcumin (DIMC), a structural analogue of curcumin, has been shown to have more stability, bioavailability, and effectiveness than its parent molecule curcumin. In this paper the radiosensitizing effect of DIMC has been investigated in A549 lung cancer cells. As compared to its parent molecule curcumin, DIMC showed a very potent radiosensitizing effect as seen by clonogenic survival assay. DIMC in combination with radiation significantly increased the apoptosis and mitotic death in A549 cells. This combinatorial treatment also lead to effective elimination of cancer stem cells. Further, there was a significant increase in cellular ROS, decrease in GSH to GSSG ratio and also significant slowdown in DNA repair when DIMC was combined with radiation. In silico docking studies and in vitro studies showed inhibition of thioredoxin reductase enzyme by DIMC. Overexpression of thioredoxin lead to the abrogation of radiosensitizing effect of DIMC underscoring the role of thioredoxin reductase in radiosensitization. Our results clearly demonstrate that DIMC can synergistically enhance the cancer cell killing when combined with radiation by targeting thioredoxin system.
authors.affiliation: Radiation Biology & Health Sciences Division, Modular Laboratories, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
authors.forename: Sundarraj
authors.initials: S
authors.lastname: Jayakumar
authors.affiliation: Radiation Biology & Health Sciences Division, Modular Laboratories, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
authors.forename: R S
authors.initials: RS
authors.lastname: Patwardhan
authors.affiliation: Radiation Biology & Health Sciences Division, Modular Laboratories, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India.
authors.forename: Debojyoti
authors.initials: D
authors.lastname: Pal
authors.affiliation: Radiation Biology & Health Sciences Division, Modular Laboratories, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India.
authors.forename: Deepak
authors.initials: D
authors.lastname: Sharma
authors.affiliation: Radiation Biology & Health Sciences Division, Modular Laboratories, Bhabha Atomic Research Centre, Trombay, Mumbai 400085, India; Homi Bhabha National Institute, Anushaktinagar, Mumbai 400094, India. Electronic address: sskumar@barc.gov.in.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Sandur
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy / Q000379:methods; D003474:Curcumin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013880:Thioredoxin-Disulfide Reductase / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D017382:Reactive Oxygen Species; C521105:dimethoxycurcumin; D013880:Thioredoxin-Disulfide Reductase; D003474:Curcumin
keywords: Cancer stem cells; Dimethoxycurcumin; Ionizing radiation; Radiosensitivity; Thioredoxin reductase