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Drugs That Inhibit The Sarcoplasmic Reticulum Ca 2+ ATPase (SERCA) and Prevention of Breast Cancer Cell Proliferation
Author(s) -
Loulousis Melanie,
Krager Stacey L,
Darcy Yuanzhao L,
Tischkau Shelley A,
Copello Julio A
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.768.4
Subject(s) - serca , thapsigargin , cyclopiazonic acid , endoplasmic reticulum , cancer cell , intracellular , chemistry , cancer research , microbiology and biotechnology , pharmacology , breast cancer , cancer , atpase , medicine , biology , biochemistry , enzyme
Breast cancer is the most common cancer in women and a leading cause of death worldwide. Pharmacological modulation of intracellular Ca 2+ homeostasis has been proposed as a potential target for therapeutic intervention for breast cancer. In this regard, thapsigargin and cyclopiazonic acid inhibit the Ca 2+ ATPase of sarcoplasmic reticulum (SERCA) that pumps Ca 2+ into the endoplasmic reticulum (ER) intracellular Ca 2+ stores and display high efficacy for killing breast cancer cells. However, these “classic” SERCA blockers are highly toxic and also kill normal cells, thereby preventing use for anticancer therapy. We have determined that new drugs in the benzothiazepine (BZT) family (K201, CGP37157), as well as agents like pimozide and sipatrigine can inhibit SERCA through a novel Ca 2+ dependent mechanism. These agents would not affect Ca 2+ sequestration in ER when cytosolic Ca 2+ levels are high, but potently inhibit this process when cytosolic Ca 2+ approaches resting cell levels, which could help prevent ER overload under pathological conditions (ischemia) and provide cellular protection in normal tissues. Therefore, we tested the effectiveness of these drugs to inhibit growth of two breast cancer cell lines, MCF‐7 and MDA‐231, in culture. Our preliminary studies indicate that K201 inhibits MCF‐7 breast cancer cell growth and synergizes with anti‐cancer drugs to increase their effectiveness in killing these cells; thus, MCF‐7 cells are not “protected” by the decreased ER Ca 2+ load provided by the SERCA inhibitors; in fact these drugs make them less viable. Building upon this data, we compared the effects of a “classic” SERCA blocker (thapsigargin) to the Ca 2+ dependent SERCA blockers above on MCF‐7 and MDA‐231 breast cancer cells. We determined that all SERCA blockers effectively disrupted the metabolic activity of MCF‐7 cells but were much less effective in MDA‐231. In MCF‐7 cells, SERCA blockers also increased the effects of chemotherapeutic drugs (cisplatin, doxorubicin). The results indicate that targeting SERCA has potential to interfere with cancer cell growth. However, our results also suggest that resistance to chemotherapy in MDA‐231 may relate to these cancer cells becoming less dependent on intracellular Ca 2+ signaling. We have also determined some of the structural characteristics that are required for BZT to block SERCA. Finally, we also found that drugs reported to do both, protection of normal cells in ischemia and inhibition of cancer cell proliferation, can also display significant SERCA blocking ability. These agents may serve as potential templates for developing new anti‐cancer drugs that target intracellular Ca 2+ homeostasis Support or Funding Information APS Frontiers in Physiology Research Fellowship to ML SIUSOM Team Development Award to SAT and JAC