Targeting heat shock response to sensitize cancer cells to proteasome and Hsp90 inhibitors

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 3; pp. 1783 - 1791
• Main Authors: ZAARUR, Nava, GABAI, Vladimir L, PORCO, John A, CALDERWOOD, Stuart, SHERMAN, Michael Y
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-02-2006
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; CHO Cells; Cricetinae; Drug Screening Assays, Antitumor; Drug Synergism; Emetine - analogs & derivatives; Heat-Shock Response; HSP90 Heat-Shock Proteins - antagonists & inhibitors; Humans; Medical sciences; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Pharmacology. Drug treatments; Proteasome Inhibitors; Structure-Activity Relationship; Tumors; Shock; Temperature; Heat; Target; Targeting; Proteasome inhibitor; Heat shock protein; Environmental factor; Malignant tumor; Tumor cell; Heat shock protein 90
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-05-3692

Novel classes of anticancer drugs, including proteasome inhibitors and Hsp90 inhibitors, potently induce heat shock proteins (Hsps). Because Hsps show antiapoptotic activities, we suggested that suppression of such induction may sensitize cancer cells to these drugs. Here, we knocked out the major heat shock transcription factor HSF-1 in several cancer cell lines using small interfering RNA and showed that such cells, which can no longer induce Hsps in response to proteasome and Hsp90 inhibitors, become more sensitive to these drugs. Furthermore, we developed a high-throughput screen for small molecules that inhibit induction of Hsps. The first step was a cell-based screen for inhibitors of Hsps-mediated luciferase refolding followed by a counterscreen for toxicity. The second step was a direct testing for inhibition of Hsp induction by immunoblotting with anti-Hsp72 antibody. After screening of 20,000 compounds from several diversity libraries, we focused on a compound we called NZ28, which potently inhibited induction of Hsps by heat shock, proteasome, and Hsp90 inhibitors in a variety of cell lines, and showed no significant toxicity. After testing of a set of analogues of NZ28, we identified a structural element that was critical for the activity. We also identified another inhibitor of the Hsp induction that was practically nontoxic. This compound, which we called emunin, strongly sensitized myeloma cells to proteasome and Hsp90 inhibitors and prostate carcinoma cells to proteasome inhibitors. This work indicates that targeting the heat shock response may facilitate use of proteasome and Hsp90 inhibitors for cancer treatment.