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ABSTRACT
Women consuming molecular iodine (I2) through seaweeds suffer the least from breast cancers. Zoledronate (Zol) is in clinical use for alleviation of bone pain in cancer patients. Triple negative breast cancers exhibit high mortality due to lack of neoadjuvant chemotherapy. I2 and Zol independently cause weak antiproliferative and apoptotic effect. So far, their combined effects have not been tested. We analyzed the effect of combination of I2 with Zol as a potent adjuvant therapeutic agent for triple negative breast cancer cells (MDA-MBA-231) and in the mice model of breast cancer. Cell viability, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, Western blotting, real-time PCR, flow cytometry, and other assays were performed for assessing cell death, calcium levels, and migration potential, respectively, in treated cells. The increased caspase 8, increased [Ca2+]c levels, and endoplasmic reticulum (ER) stress resulted in apoptosis. Real time and fluorescence-based analysis demonstrated that the combination treatment targets ER Ca2+ homeostasis chaperons leading to apoptosis. Combination therapy reduces metalloproteinases 2 and 9, inhibits invasion/migration of cells, and prevents growth of tumor in mice.
I2 + Zol combination treatment induces synergistic increase in ER-mediated apoptosis, reduces invasion/migration potential of MDA-MB-231 cells, and exhibits antiproliferative property in vivo demonstrating its potential as combination therapy.
Abbreviations
| Bax | = | (Bcl2-associated X protein) |
| Bcl2 | = | (B-cell lymphoma 2) |
| Bcl-XL | = | (B-cell lymphoma-extra large) |
| [Ca2+] | = | (Cytosolic calcium) |
| Cyto C | = | (Cytochrome C) |
| COX4 | = | (Cyclooxygenase 4) |
| CHOP | = | (C/EBP homologous protein) |
| GADD153 | = | (Growth arrest and DNA damage inducible gene 153) |
| GRP78 | = | (Glucose-regulated protein) |
| I− | = | (Iodide) |
| IP3R1, IP3R2, and IP3R3 | = | (Inositol-1,4,5-triphosphate receptor type 1, type2, and type3) |
| LC3 | = | (Light chain protein 3) |
| MMP | = | (Matrix metalloproteinase) |
| MPT | = | (Mitochondrial membrane permeability transition) |
| ROS | = | (Reactive oxygen species) |
| TUNEL | = | (Terminal deoxynucleotidyl transferase dUTP nick end labeling) |
| Xbp1 | = | (X-box-binding protein 1) |
| Zol | = | (Zoledronate) |
| Z-IETD-FMK | = | (Z-Ile-Glu(OMe)-Thr-Asp(OMe)-fluoro methyl ketone) |
| Z-VAD-FMK | = | (Z-Val-Ala-Asp-fluoromethyl ketone) |
Funding
This work was supported by the Department of Biotechnology, New Delhi (Grant BT/PR 9822/MED/30/42/2007 to Godbole M M) and research fellowship from the Indian Council of Medical Research, New Delhi (3/2/152/2008/NCD-III to Ranu Tripathi).