Concurrent exposure to heat shock and H7 synergizes to trigger breast cancer cell apoptosis while sparing normal cells.
Most cancer therapies, including chemotherapy, kill tumor cells by inducing apoptosis. Consequently, the propensity of tumor cells to evade apoptotic signals contributes to therapeutic resistance. Here we show that breast cancer cells exhibiting a highly resistant phenotype undergo apoptosis when exposed to concurrent heat shock and H7, a potent serine/threonine kinase inhibitor. The anti-tumor effects of this combination are synergistic as neither treatment alone adversely affects breast cancer cell growth/survival. In contrast, non-malignant breast epithelial and hematopoietic progenitor cells are resistant to this combination therapy, thereby excluding non-specific cytotoxicity as the cause of tumor cell apoptosis. Heat or other cell stresses, including chemotherapy, preferentially enhance heat shock protein (hsp) synthesis, which serves to protect cells from potentially lethal consequences of heat shock stimuli. Ectopic overexpression of hsps in breast cancer cells protects against chemotherapy-induced apoptosis. Furthermore, increased hsps in primary breast cancers correlates with resistance to therapy and decreased survival. Stress-induced hsp synthesis is mediated by heat shock transcription factor 1 (HSF1). To simulate hsp overexpressing primary breast cancers, a number of breast cancer cell lines were transfected with HSF1d202-316, a constitutively activated form of HSF1 that leads to baseline overexpression of hsps in the absence of stress. Importantly, HSF1d202-316 transfected breast cancer cells undergo apoptosis following concurrent heat shock and H7. In light of its tumor selective activity against breast cancer cells that exhibit a highly resistant phenotype, concurrent H7 and heat shock warrants further investigation as a potential cancer therapy.
Xia, W; Hardy, L; Liu, L; Zhao, S; Goodman, M; Voellmy, R; Spector, NL
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