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Inhibition of autophagy stimulate molecular iodine-induced apoptosis in hormone independent breast tumors.

Abstract

Estrogen receptor negative (ER(-ve)) and p53 mutant breast tumors are highly aggressive and have fewer treatment options. Previously, we showed that molecular Iodine (I(2)) induces apoptosis in hormone responsive MCF-7 breast cancer cells, and non-apoptotic cell death in ER(-ve)-p53 mutant MDA-MB231 cells (Shrivastava, 2006). Here we show that I(2) (3 μM) treatment enhanced the features of autophagy in MDA-MB231 cells. Since autophagy is a cell survival response to most anti-cancer therapies, we used both in vitro and in vivo systems to determine whether ER(-ve) mammary tumors could be sensitized to I(2)-induced apoptosis by inhibiting autophagy. Autophagy inhibition with chloroquine (CQ) and inhibitors for PI3K (3MA, LY294002) and H+/ATPase (baflomycin) resulted in enhanced cell death in I(2) treated MDA-MB231 cells. Further, CQ (20 μM) in combination with I(2), showed apoptotic features such as increased sub-G1 fraction (∼5-fold), expression of cleaved caspase-9 and -3 compared to I(2) treatment alone. Flowcytometry of I(2) and CQ co-treated cells revealed increase in mitochondrial membrane permeability (p<0.01) and translocation of cathepsin D activity to cytosol relative to I(2) treatment. For in vivo studies ICRC mice were transplanted subcutaneously with MMTV-induced mammary tumors. A significant reduction in tumor volumes, as measured by MRI, was found in I(2) and CQ co-treated mice relative to I(2) or vehicle treated mice. These data indicate that inhibition of autophagy renders ER(-ve) breast tumor cells more sensitive to I(2) induced apoptosis. Thus, I(2) together with autophagy inhibitor could have a potential tumorostatic role in ER(-ve) aggressive breast tumors that may be evaluated in future studies.

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  • Authors+Show Affiliations

    ,

    Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.

    , , , , , , ,

    Source

    MeSH

    Animals
    Antineoplastic Agents
    Apoptosis
    Autophagy
    Breast Neoplasms
    Caspase 3
    Caspase 9
    Cathepsin D
    Cell Line, Tumor
    Chloroquine
    Cytosol
    Estrogens
    Female
    Humans
    Iodine
    Mice
    Mice, Inbred ICR
    Mitochondrial Membranes
    Permeability
    Protein Transport
    Receptors, Estrogen
    Tumor Suppressor Protein p53

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22027149

    Citation

    TY - JOUR T1 - Inhibition of autophagy stimulate molecular iodine-induced apoptosis in hormone independent breast tumors. AU - Singh,Preeti, AU - Godbole,Madan, AU - Rao,Geeta, AU - Annarao,Sanjay, AU - Mitra,Kalyan, AU - Roy,Raja, AU - Ingle,Arvind, AU - Agarwal,Gaurav, AU - Tiwari,Swasti, Y1 - 2011/10/18/ PY - 2011/10/07/received PY - 2011/10/11/accepted PY - 2011/10/27/entrez PY - 2011/10/27/pubmed PY - 2012/1/13/medline SP - 181 EP - 6 JF - Biochemical and biophysical research communications JO - Biochem. Biophys. Res. Commun. VL - 415 IS - 1 N2 - Estrogen receptor negative (ER(-ve)) and p53 mutant breast tumors are highly aggressive and have fewer treatment options. Previously, we showed that molecular Iodine (I(2)) induces apoptosis in hormone responsive MCF-7 breast cancer cells, and non-apoptotic cell death in ER(-ve)-p53 mutant MDA-MB231 cells (Shrivastava, 2006). Here we show that I(2) (3 μM) treatment enhanced the features of autophagy in MDA-MB231 cells. Since autophagy is a cell survival response to most anti-cancer therapies, we used both in vitro and in vivo systems to determine whether ER(-ve) mammary tumors could be sensitized to I(2)-induced apoptosis by inhibiting autophagy. Autophagy inhibition with chloroquine (CQ) and inhibitors for PI3K (3MA, LY294002) and H+/ATPase (baflomycin) resulted in enhanced cell death in I(2) treated MDA-MB231 cells. Further, CQ (20 μM) in combination with I(2), showed apoptotic features such as increased sub-G1 fraction (∼5-fold), expression of cleaved caspase-9 and -3 compared to I(2) treatment alone. Flowcytometry of I(2) and CQ co-treated cells revealed increase in mitochondrial membrane permeability (p<0.01) and translocation of cathepsin D activity to cytosol relative to I(2) treatment. For in vivo studies ICRC mice were transplanted subcutaneously with MMTV-induced mammary tumors. A significant reduction in tumor volumes, as measured by MRI, was found in I(2) and CQ co-treated mice relative to I(2) or vehicle treated mice. These data indicate that inhibition of autophagy renders ER(-ve) breast tumor cells more sensitive to I(2) induced apoptosis. Thus, I(2) together with autophagy inhibitor could have a potential tumorostatic role in ER(-ve) aggressive breast tumors that may be evaluated in future studies. SN - 1090-2104 UR - https://www.unboundmedicine.com/medline/citation/22027149/Inhibition_of_autophagy_stimulate_molecular_iodine_induced_apoptosis_in_hormone_independent_breast_tumors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(11)01851-1 ER -