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. 2019 May 3;8:e44306. doi: 10.7554/eLife.44306

Figure 6. HDAC inhibitors and chemotherapy synergistically induce tumor death.

(A) KURAMOCHI, HEY, SKOV3 and OVTOKO cells were treated with cisplatin (2 μM) and HDAC inhibitors (panobinostat: 50 nM; romidepsin: 25 nM) as indicated, and cell lysates were analyzed by immunoblotting. (B) Heatmaps of bliss synergy scores demonstrated synergistic activities of cisplatin and HDAC inhibitors in KURAMOCHI (cisplatin: 0, 0.25, 0.5, 1, 2, 4, 8 μM; panobinostat: 0, 12.5, 25, 50, 100, 200, 400 nM; romidepsin: 0, 0.5, 1, 2, 4, 8, 16 nM), HEY (cisplatin: 0, 0.1, 0.3, 1, 3, 10, 30 μM; panobinostat: 0, 1, 3, 10, 30, 100, 300 nM; romidepsin: 0, 0.0625, 0.125, 0.25, 0.5, 1, 2 nM), SKOV3 (cisplatin: 0, 0.1, 0.3, 1, 3, 10, 30 μM; panobinostat: 0, 1, 3, 10, 30, 100, 300 nM; romidepsin: 0, 0.0625, 0.125, 0.25, 0.5, 1, 2 nM) and OVTOKO (cisplatin: 0, 0.25, 0.5, 1, 2, 4, 8 μM; panobinostat: 0, 12.5, 25, 50, 100, 200, 400 nM; romidepsin: 0, 0.5, 1, 2, 4, 8, 16 nM). (C) KURAMOCHI, HEY, SKOV3 and OVTOKO cells were treated with cisplatin (2 μM) and HDAC inhibitors (panobinostat: 50 nM; romidepsin: 25 nM) as indicated, and were analyzed by crystal violet staining. (D) Tumor growth curves were shown for the PDX EOC-002 model treated with indicated regimens. The right panel indicated relative tumor volume changes at the end point versus the treatment start point. (E) Tumor growth curves were shown for the PDX EOC-004 model treated with indicated regimens. The right panel indicated relative tumor volume changes at the end point versus the treatment start point. (F) Representative images of hematoxylin and eosin (H&E) and immunohistochemistry staining for PAX8, Ki-67 or cleaved PARP.

Figure 6.

Figure 6—figure supplement 1. HDAC inhibitors induced cell pyroptosis and restrained chemo-resistant ovarian cancer cell proliferation.

Figure 6—figure supplement 1.

(A) LDH release from ovarian cancer cells treated with indicated compounds (cisplatin: 2 μM; panobinostat: 50 nM; romidepsin: 25 nM). (B) Chemo-sensitive or resistant SKOV3 cells were treated with panobinostat or romidepsin, and analyzed by immunoblotting as indicated. HDAC inhibitors reduced PAX8 protein levels in dose- (treatment duration: 48 hr) and time- (panobinostat concentration: 100 nM; romidepsin concentration: 50 nM) dependent manners. (C) Chemo-sensitive or resistant SKOV3 cells were treated with cisplatin, panobinostat or romidepsin, and analyzed by crystal violet staining. (D) Boxplots of PAX8 gene expression in 221 PDX models from seven different types of solid cancers.