Figure 4. OV tumours are sensitive to disruption of proteostasis.

(a) Low passage patient-derived OV (LPPDOV) ascites cells from a patient who failed cisplatin–docetaxel chemotherapy were injected i.p. into Nu/nu mice, allowed to disseminate and grow for 10 days, and then treated with control 50% PEG400 or with COAST (Combination of Autophagy Selective Therapeutics: chloroquine 30 mg kg⁻¹, nelfinavir 250 mg kg⁻¹, rapamycin 2.24 mg kg⁻¹, dasatinib 4 mg kg⁻¹ and metformin 150 mg kg⁻¹ in 50% PEG400) daily for 15 days. An additional control group was treated with cisplatin/docetaxel chemotherapy (injected i.p. with 1 mg kg⁻¹ cisplatin and 2.5 mg kg⁻¹ docetaxel once per week starting at the first control treatment day for 2 weeks). Upon harvest, all visible and palpable tumours in the peritoneum space were dissected, counted and weighed, as were mouse spleens. (b) C57BL/6 immunocompetent mice were injected i.p. with ID8-IP-mCherry cells (N=8 per group). After 2 weeks to permit tumour establishment, mice were orally gavaged daily with control 50% PEG400, with COAST, or chloroquine and nelfinavir alone. At 14 days, control mice developed ascites. All groups were killed, ascites were measured and tumour burden assayed by native mCherry fluorescence. Ovaries are displayed for all mice, and any additional tumor fluorescence observed is displayed on the right panel with labels ‘P' for peritoneal wall growth and ‘L' for liver. (c) Nu/nu mice with 100 mm³ subcutaneous OVCAR3 tumours were gavaged with COAST or control and tumour growth monitored by digital calipers for 7 days. Tumours were then dissected, weighed and (d) subjected to immunoblotting for autophagosomal Lc3-II and the ER stress marker Grp78 (mean±s.e.m. N=7 mice per group). *P<0.05, **P<0.01, ***P<0.001 by Wilcoxon rank-sum test.