Combination of HSP90 and autophagy inhibitors promotes hepatocellular carcinoma apoptosis following incomplete thermal ablation

Chen,Fen; Xie,Haiyang; Bao,Haiwei; Violetta,Laurencia; Zheng,Shusen

doi:10.3892/mmr.2020.11080

Combination of HSP90 and autophagy inhibitors promotes hepatocellular carcinoma apoptosis following incomplete thermal ablation

Authors:
- Fen Chen
- Haiyang Xie
- Haiwei Bao
- Laurencia Violetta
- Shusen Zheng
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Affiliations: Department of Ultrasound, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310002, P.R. China, Key Laboratory of Combined Multi‑organ Transplantation, Ministry of Public Health, Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310002, P.R. China, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Zhejiang University, Hangzhou, Zhejiang 310002, P.R. China, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310002, P.R. China
Published online on: April 21, 2020 https://doi.org/10.3892/mmr.2020.11080
Pages: 337-343
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study evaluated the effect of combining inhibitors (17‑AAG) of heat shock protein 90 (HSP90) and autophagy (3‑MA) on apoptosis using an incomplete thermal ablation animal model. A total of 28 orthotopic mice with hepatocellular carcinoma were randomly divided into 4 groups to receive different drug interventions. Following palliative laser ablation, changes in autophagy, apoptosis and Akt/mTOR expression levels were assessed in tumors. Compared with the controls, the 17‑AAG‑treated mice exhibited significantly decreased expression levels of phosphorylated (p)‑Akt and p‑mTOR with enhanced autophagy and apoptosis; no marked increases in the expression levels of p‑Akt and p‑mTOR were observed in the 3‑MA‑treated mice, with no significant changes in autophagy; however, apoptosis was enhanced. No significant decreases in p‑Akt and p‑mTOR or any increase in autophagy were observed in the mice receiving a combination of 17‑AAG and 3‑MA, but they did exhibit a marked increase in apoptosis. Compared with 17‑AAG alone, the combination of 17‑AAG and 3‑MA resulted in a marked increase in apoptosis without enhanced autophagy. In the incomplete ablation model, the effects of autophagy and apoptosis are antagonistic. The combined use of 17‑AAG and 3‑MA can significantly promote apoptosis and is worthy of further study.

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1	Yun KC, Rhim H and Noh S: Radiofrequency ablation versus surgical resection as primary treatment of hepatocellular carcinoma meeting the Milan criteria: A systematic review. J Gastroenterol Hepatol. 26:1354–1360. 2011.PubMed/NCBI
2	Hermida M, Cassinotto C, Piron L, Assenat E, Pageaux GP, Escal L, Pierredon-Foulongne MA, Verzilli D, Jaber S and Guiu B: Percutaneous thermal ablation of hepatocellular carcinomas located in the hepatic dome using artificial carbon dioxide pneumothorax: Retrospective evaluation of safety and efficacy. Int J Hyperthemia. 35:90–96. 2018. View Article : Google Scholar
3	Medhat E, Abdel Aziz A, Nabeel M, Elbaz T, Zakaria Z, Shousha H, Amer A, Fouad Fathalah W, Maher R and Musa S: Value of microwave ablation in treatment of large lesions of hepatocellular carcinoma. J Dig Dis. 16:456–463. 2015. View Article : Google Scholar : PubMed/NCBI
4	Schueller G, Kettenbach J, Sedivy R, Stift A, Friedl J, Gnant M and Lammer J: Heat shock protein expression induced by percutaneous radiofrequency ablation of hepatocellular carcinoma in vivo. Int J Oncol. 24:609–613. 2004.PubMed/NCBI
5	Hinz S, Tepel J, Röder C, Kalthoff H and Becker T: Profile of serum factors and disseminated tumor cells before and after radiofrequency ablation compared to resection of colorectal liver metastases-a pilot study. Anticancer Res. 35:2961–2967. 2015.PubMed/NCBI
6	Rai R, Richardson C, Flecknell P, Robertson H, Burt A and Manas DM: Study of apoptosis and heat shock protein (HSP) expression in hepatocytes following radiofrequency ablation (RFA). J Surg Res. 129:147–151. 2005. View Article : Google Scholar : PubMed/NCBI
7	Yang W, Ahmed M, Tasawwar B, Levchenko T, Sawant RR, Collins M, Signoretti S, Torchilin V and Goldberg SN: Radiofrequency ablation combined with liposomal quercetin to increase tumour destruction by modulation of heat shock protein production in a small animal model. Int J Hyperthermia. 27:527–538. 2011. View Article : Google Scholar : PubMed/NCBI
8	Schueller G, Kettenbach J, Sedivy R, Bergmeister H, Stift A, Fried J, Gnant M and Lammer J: Expression of heat shock proteins in human hepatocellular carcinoma after radiofrequency ablation in an animal model. Oncol Rep. 12:495–499. 2004.PubMed/NCBI
9	He W, Ye X, Huang X, Lel W, You L, Wang L, Chen X and Qian W: Hsp90 inhibitor, BIIB021, induces apoptosis and autophagy by regulating mTOR-Ulk1 pathway in imatinib-sensitive and-resistant chronic myeloid leukemia cells. Int J Oncol. 48:1710–1720. 2016. View Article : Google Scholar : PubMed/NCBI
10	Leng AM, Liu T, Yang J, Cui JF, Li XH, Zhu YN, Xiong T, Zhang G and Chen Y: The apoptotic effect and associated signalling of HSP90 inhibitor 17-DMAG in hepatocellular carcinoma cells. Cell Biol Int. 36:893–899. 2012. View Article : Google Scholar : PubMed/NCBI
11	Liu X, Chen S, Tu J, Cai W and Xu Q: HSP90 inhibits apoptosis and promotes growth by regulating HIF-1α abundance in hepatocellular carcinoma. Int J Mol Med. 37:825–835. 2016. View Article : Google Scholar : PubMed/NCBI
12	Liu X, Ban LL, Luo G, Li ZY, Li YF, Zhou YC, Wang XC, Jin CG, Ye JG, Ma DD, et al: Acquired resistance to HSP90 inhibitor 17-AAG and increased metastatic potential are associated with MUC1 expression in colon carcinoma cells. Anticancer Drugs. 27:417–426. 2016. View Article : Google Scholar : PubMed/NCBI
13	Chen Y, Youn P, Pysher TJ, Scaife CL and Furgeson DY: Tumour eradication using synchronous thermal ablation and Hsp90 chemotherapy with protein engineered triblock biopolymer-geldanamycin conjugates. Int J Hyperthermia. 30:550–564. 2014. View Article : Google Scholar : PubMed/NCBI
14	Lang SA, Moser C, Fichnter-Feigl S, Schachtschneider P, Hellerbrand C, Schmitz V, Schlitt HJ, Geissler EK and Stoeltzing O: Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of hepatocellular carcinoma in mice. Hepatology. 49:523–532. 2009. View Article : Google Scholar : PubMed/NCBI
15	Webber PJ, Park C, Qui M, Ramalingam SS, Khuri FR, Fu H and Du Y: Combination of heat shock protein 90 and focal adhesion kinase inhibitors synergistically inhibits the growth of non-small cell lung cancer cells. Oncoscience. 2:765–776. 2015.PubMed/NCBI
16	Yang R, Tang Q, Miao F, An Y, Li M, Han Y, Wang X, Wang J, Liu P and Chen R: Inhibition of heat-shock protein 90 sensitizes liver cancer stem-like cells to magnetic hyperthermia and enhances anti-tumor effect on hepatocellular carcinoma-burdened nude mice. Int J Nanomedicine. 10:7345–7358. 2015. View Article : Google Scholar : PubMed/NCBI
17	Moussa M, Goldberg SN, Kumar G, Sawant RR, Levchenko T, Torchilin V and Ahmed M: Radiofrequency ablation-induced upregulation of hypoxia-inducible factor-1α can be suppressed with adjuvant bortezomib or liposomal chemotherapy. J Vasc Interv Radiol. 25:1972–1982. 2014. View Article : Google Scholar : PubMed/NCBI
18	Chen F, Bao H, Xie H, Tian G and Jiang T: Heat shock protein expression and autophagy after incomplete thermal ablation and their correlation. Int J Hyperthermia. 36:95–103. 2019. View Article : Google Scholar : PubMed/NCBI
19	Zhang R, Luo D, Miao R, Bai L, Ge Q, Sessa WC and Min W: Hsp90-Akt phosphorylates ASK1 and inhibits ASK1-mediated apoptosis. Oncogene. 24:3954–3963. 2005. View Article : Google Scholar : PubMed/NCBI
20	Sato S, Fujita N and Tsuruo T: Modulation of Akt kinase activity by binding to Hsp90. Proc Natl Acad Sci USA. 97:10832–10837. 2000. View Article : Google Scholar : PubMed/NCBI
21	Oral O, Akkoc Y, Bayraktar O and Gozuacik D: Physiological and pathological significance of the molecular cross-talk between autophagy and apoptosis. Histol Histopathol. 31:479–498. 2016.PubMed/NCBI
22	Heras-Sandoval D, Pérez-Rojas JM, Hernández-Damián J and Pedraza-Chaverri J: The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal. 26:2694–2701. 2014. View Article : Google Scholar : PubMed/NCBI
23	Nazim UM and Park SY: Attenuation of autophagy flux by 6-shogaol sensitizes human liver cancer cells to TRAIL-induced apoptosis via p53 and ROS. Int J Mol Med. 43:701–708. 2019.PubMed/NCBI
24	Mukhopadhyay S, Panda PK, Sinha N, Das DN and Bhutia SK: Autophagy and apoptosis: Where do they meet? Apoptosis. 19:555–566. 2014. View Article : Google Scholar : PubMed/NCBI
25	Mariño G, Niso-Santano M, Baehrecke EH and Kroemer G: Self-consumption: The interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol. 15:81–94. 2014. View Article : Google Scholar : PubMed/NCBI
26	Talaei S, Mellatyar H, Asadi A, Akbarzadeh A, Sheervalilou R and Zarghami N: Spotlight on 17-AAG as an Hsp90 inhibitor for molecular targeted cancer treatment. Chem Biol Drug Des. 93:760–786. 2019. View Article : Google Scholar : PubMed/NCBI
27	Walker AR, Klisovic R, Johnston JS, Jiang Y, Geyer S, Kefauver C, Binkley P, Byrd JC, Grever MR, Garzon R, et al: Pharmacokinetics and dose escalation of the heat shock protein inhibitor 17-allyamino-17-demethoxygeldanamycin in combination with bortezomib in relapsed or refractory acute myeloid leukemia. Leuk Lymphoma. 54:1996–2002. 2013. View Article : Google Scholar : PubMed/NCBI
28	Kaufmann SH, Karp JE, Litzow MR, Mesa RA, Hogan W, Steensma DP, Flatten KS, Loegering DA, Schneider PA, Peterson KL, et al: Phase I and pharmacological study of cytarabine and tanespimycin in relapsed and refractory acute leukemia. Haematologica. 96:1619–1626. 2011. View Article : Google Scholar : PubMed/NCBI
29	Heath EI, Hillman DW, Vaishampayan U, Sheng S, Sarkar F, Harper F, Gaskins M, Pitot HC, Tan W, Ivy SP, et al: A phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with hormone-refractory metastatic prostate cancer. Clin Cancer Res. 14:7940–7946. 2018. View Article : Google Scholar
30	Pacey S, Gore M, Chao D, Banerji U, Larkin J, Sarker S, Owen K, Asad Y, Raynaud F, Walton M, et al: A Phase II trial of 17-allylamino, 17-demethoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma. Invest New Drugs. 30:341–349. 2012. View Article : Google Scholar : PubMed/NCBI
31	Strozyk E and Kulms D: The role of AKT/mTOR pathway in stress response to UV-irradiation: Implication in skin carcinogenesis by regulation of apoptosis, autophagy and senescence. Int J Mol Sci. 14:15260–15285. 2013. View Article : Google Scholar : PubMed/NCBI
32	Janku F, Mcconkey DJ, Hong DS and Kurzrock R: Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol. 8:528–539. 2011. View Article : Google Scholar : PubMed/NCBI