Zoledronate and Molecular Iodine Cause Synergistic Cell Death in Triple Negative Breast Cancer through Endoplasmic Reticulum Stress.
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 [Ca(2+)]c levels, and endoplasmic reticulum (ER) stress resulted in apoptosis. Real time and fluorescence-based analysis demonstrated that the combination treatment targets ER Ca(2+) 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.
a Department of Endocrinology , Sanjay Gandhi Postgraduate Institute of Medical Sciences , Raebareli Road, Lucknow , India.
Ranu
R
Tripathi
a Department of Endocrinology , Sanjay Gandhi Postgraduate Institute of Medical Sciences , Raebareli Road, Lucknow , India.
Preeti
P
Singh
b Department of Molecular Medicine and Biotechnology , Sanjay Gandhi Postgraduate Institute of Medical Sciences , Raebareli Road, Lucknow , India.
Aru
A
Singh
b Department of Molecular Medicine and Biotechnology , Sanjay Gandhi Postgraduate Institute of Medical Sciences , Raebareli Road, Lucknow , India.
Megha
M
Chagtoo
c Department of Endocrine Surgery , Sanjay Gandhi Postgraduate Institute of Medical Sciences , Raebareli Road, Lucknow , India.
Sajid
S
Khan
b Department of Molecular Medicine and Biotechnology , Sanjay Gandhi Postgraduate Institute of Medical Sciences , Raebareli Road, Lucknow , India.
Swasti
S
Tiwari
d Department of Endocrinology , Central Drug Research Institute , Lucknow , India.
Gaurav
G
Agarwal
c Department of Endocrine Surgery , Sanjay Gandhi Postgraduate Institute of Medical Sciences , Raebareli Road, Lucknow , India.
Syed Musthapa
SM
Meeran
a Department of Endocrinology , Sanjay Gandhi Postgraduate Institute of Medical Sciences , Raebareli Road, Lucknow , India.|b Department of Molecular Medicine and Biotechnology , Sanjay Gandhi Postgraduate Institute of Medical Sciences , Raebareli Road, Lucknow , India.
Madan M
MM
Godbole
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007455:Iodine / Q000008:administration & dosage; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D018832:Molecular Chaperones / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
D004164:Diphosphonates; D007093:Imidazoles; D018832:Molecular Chaperones; D000077211:Zoledronic Acid; D007455:Iodine; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D002118:Calcium