Inhibition of autophagy stimulate molecular iodine-induced apoptosis in hormone independent breast tumors
2011
Singh, Preeti | Godbole, Madan | Rao, Geeta | Annarao, Sanjay | Mitra, Kalyan | Roy, Raja | Ingle, Arvind | Agarwal, Gaurav | Tiwari, Swasti
Estrogen receptor negative (ER⁻ᵛᵉ) and p53 mutant breast tumors are highly aggressive and have fewer treatment options. Previously, we showed that molecular Iodine (I₂) 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 I₂ (3μM) 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 I₂-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 I₂ treated MDA-MB231 cells. Further, CQ (20μM) in combination with I₂, showed apoptotic features such as increased sub-G1 fraction (∼5-fold), expression of cleaved caspase-9 and -3 compared to I₂ treatment alone. Flowcytometry of I₂ and CQ co-treated cells revealed increase in mitochondrial membrane permeability (p<0.01) and translocation of cathepsin D activity to cytosol relative to I₂ 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 I₂ and CQ co-treated mice relative to I₂ or vehicle treated mice. These data indicate that inhibition of autophagy renders ER⁻ᵛᵉ breast tumor cells more sensitive to I₂ induced apoptosis. Thus, I₂ 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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