Numerous cancer studies with proteasome inhibitor and SAHA combinations
Target / Drugs / Study / Result / Mechanism / Ref
Breast cancer / BTZ + SAHA + clarithromycin / MDA-MB-231, BT474, MDB-MB-468, CHOP-KO-DR / Enhanced apoptosis with increased CHOP / 1
Cervical carcinoma / BTZ + SAHA / HeLa cells / Increased apoptosis and activated caspase3, increased bax/bcl-2 ratio expression, and reduced NF-κB and AKT / 2
Cervical carcinoma / BTZ + SAHA / HPV positive and negative cell lines and HeLa xenografts / Synergistic killing of HPVpositive, not HPVnegative, cervical cancer lines and reduced in vivo tumor growth / 3
Colon cancer / BTZ + SAHA / HCT116, HT29 cell lines / Synergistic decrease in proliferation and increased apoptosis / 4
Esophageal cancer / BTZ + SAHA / TE2, SKGT4 cell lines / Decreased cell invasion and epithelia-mesenchymal transistion / 5
Recurrent glioblastoma / BTZ + SAHA / Phase II / One partial response observed out of 34 patients / 6
Malignant glioma / BTZ + SAHA / Primary cells from GBM patients and glioma cell lines / Enhanced apoptosis, mitochondrial injury and ROS / 7
Head and neck squamous cell carcinoma / CFZ + SAHA / UMSCC-1, Cal33 cell lines / Synergistic cell death and inhibition of colony formation / 8
Hepatoma / BTZ + SAHA / HepG2, Huh6 cell lines / Synergistic apoptosis with increased c-Jun, FasL, and BclXs / 9
T-cell leukemia / CFZ + SAHA / Jurkat cells / Increased ROS and apoptosis, increased cytochrome c release, caspase9, 3 activation, and cleaved PARP / 10
Non-small cell lung cancer / BTZ + SAHA / H157, H358, H460, and A549 cells / Increased ROS and apoptosis / 11
Non-small cell lung cancer / BTZ + SAHA / Phase I / 6 of 20 patients had >60% tumor necrosis / 12
Primary effusion lymphoma / BTZ + SAHA / UM-PEL-1 cells and xenografts / Synergism with early acetylation of p53 and reduced interaction with MDM2 / 13
Mantle cell lymphoma / BTZ + SAHA / JeKo-1, Granta-519, and Hbl-2 cells / Synergism with increased ROS, increased caspase3, 8, 9 activity, and reduced NF-κB / 14
Mantle cell lymphoma / CFZ + SAHA / Six MCL cell lines, primary MCL cells, and MCL xenograft model / Enhanced lethality with JNK1/2 activation, increased ROS and G2M arrest. Significant antitumor activity in vivo / 15
Cutaneous T cell lymphoma / BTZ + SAHA / SeAx, Hut-78, MyLA, and HH cells / Synergistic cytotoxic effects with upregulation of p21, p27 and P-p38 and reduced VEGF / 16
Diffuse large B-cell lymphoma / CFZ + SAHA / Five GC- and activated B-cell-like DLBCL cells and OCI-LY10 xenograft model / Increased mitochondrial injury, caspase activation, and apoptosis with JNK and p38 activation, NF-κB inhibition / 17
Multiple myeloma / BTZ + SAHA / Phase III / Prolonged PFS relative to BTZ and placebo / 18
Multiple myeloma / BTZ + SAHA / MM-1S cells / Enhanced antitumor activity / 19
Nasopharyngeal carcinoma / BTZ + SAHA / Various NPC cell lines and xenografts / Synergistic in vitro killing, increased apoptosis and suppressed growth of NPC xenografts / 20
Pancreatic cancer / BTZ + SAHA / HPDE6-E6E7 and L3.6pl cells and xenographs / HDAC 6 mediated inhibition of BTZ-induced aggresomes results in increased apoptosis / 21
Pancreatic cancer / BTZ + SAHA + gemcitabine / MiaPaCa-2 and ASPC-1 / Decreased NF-κB, P-AKT, with decreased proliferation in vivo and in vitro / 22
Prostate cancer / BTZ + SAHA / LNCaP, PC-3, DU145 cell lines and xenografts / Enhanced apoptosis, inhibited cell growth in vitro and in vivo / 23
Renal cancer / BTZ + SAHA / Caki-1, ACHN, A-498, 786-O, 769-P cells and xenografts / Increased apoptosis, decreased colony formation and significant in vivo activity / 24
Solid tumors in children / BTZ + SAHA / Phase I / No objective responses / 25
Advanced solid tumors / BTZ + SAHA / Phase I / Stable disease observed in patients with sarcoma, colorectal adenocarcinoma, GIST / 26
Advanced malignancies / BTZ + SAHA / Phase I / Objective response in one NSCLC and one treatment-refractory soft tissue sarcoma / 27
Melanoma, pancreatic, and NSCLC caner / Marizomib + SAHA / Phase I / In vitro synergy. Clinical study showed no increased toxicity / 28
REFERENCES
1. Komatsu S, Moriya S, Che XF, Yokoyama T, Kohno N, Miyazawa K. Combined treatment with SAHA, bortezomib, and clarithromycin for concomitant targeting of aggresome formation and intracellular proteolytic pathways enhances ER stress-mediated cell death in breast cancer cells. Biochem Biophys Res Commun. 2013;437: 41-47.
2. Jiang Y, Wang Y, Su Z, et al. Synergistic induction of apoptosis in HeLa cells by the proteasome inhibitor bortezomib and histone deacetylase inhibitor SAHA. Mol Med Rep. 2010;3: 613-619.
3. Lin Z, Bazzaro M, Wang MC, Chan KC, Peng S, Roden RB. Combination of proteasome and HDAC inhibitors for uterine cervical cancer treatment. Clin Cancer Res. 2009;15: 570-577.
4. Pitts TM, Morrow M, Kaufman SA, Tentler JJ, Eckhardt SG. Vorinostat and bortezomib exert synergistic antiproliferative and proapoptotic effects in colon cancer cell models. Mol Cancer Ther. 2009;8: 342-349.
5. Taylor MD, Liu Y, Nagji AS, Theodosakis N, Jones DR. Combined proteasome and histone deacetylase inhibition attenuates epithelial-mesenchymal transition through E-cadherin in esophageal cancer cells. J Thorac Cardiovasc Surg. 2010;139: 1224-1232, 1232.e1221.
6. Friday BB, Anderson SK, Buckner J, et al. Phase II trial of vorinostat in combination with bortezomib in recurrent glioblastoma: a north central cancer treatment group study. Neuro Oncol. 2012;14: 215-221.
7. Premkumar DR, Jane EP, Agostino NR, DiDomenico JD, Pollack IF. Bortezomib-induced sensitization of malignant human glioma cells to vorinostat-induced apoptosis depends on reactive oxygen species production, mitochondrial dysfunction, Noxa upregulation, Mcl-1 cleavage, and DNA damage. Mol Carcinog. 2013;52: 118-133.
8. Zang Y, Kirk CJ, Johnson DE. Carfilzomib and oprozomib synergize with histone deacetylase inhibitors in head and neck squamous cell carcinoma models of acquired resistance to proteasome inhibitors. Cancer Biol Ther. 2014;15.
9. Emanuele S, Lauricella M, Carlisi D, et al. SAHA induces apoptosis in hepatoma cells and synergistically interacts with the proteasome inhibitor Bortezomib. Apoptosis. 2007;12: 1327-1338.
10. Gao M, Gao L, Tao Y, et al. Proteasome inhibitor carfilzomib interacts synergistically with histone deacetylase inhibitor vorinostat in Jurkat T-leukemia cells. Acta Biochim Biophys Sin (Shanghai). 2014;46: 484-491.
11. Denlinger CE, Rundall BK, Jones DR. Proteasome inhibition sensitizes non-small cell lung cancer to histone deacetylase inhibitor-induced apoptosis through the generation of reactive oxygen species. J Thorac Cardiovasc Surg. 2004;128: 740-748.
12. Jones DR, Moskaluk CA, Gillenwater HH, et al. Phase I trial of induction histone deacetylase and proteasome inhibition followed by surgery in non-small-cell lung cancer. J Thorac Oncol. 2012;7: 1683-1690.
13. Bhatt S, Ashlock BM, Toomey NL, et al. Efficacious proteasome/HDAC inhibitor combination therapy for primary effusion lymphoma. J Clin Invest. 2013;123: 2616-2628.
14. Heider U, von Metzler I, Kaiser M, et al. Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in mantle cell lymphoma. Eur J Haematol. 2008;80: 133-142.
15. Dasmahapatra G, Lembersky D, Son MP, et al. Carfilzomib interacts synergistically with histone deacetylase inhibitors in mantle cell lymphoma cells in vitro and in vivo. Mol Cancer Ther. 2011;10: 1686-1697.
16. Heider U, Rademacher J, Lamottke B, et al. Synergistic interaction of the histone deacetylase inhibitor SAHA with the proteasome inhibitor bortezomib in cutaneous T cell lymphoma. Eur J Haematol. 2009;82: 440-449.
17. Dasmahapatra G, Lembersky D, Kramer L, et al. The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo. Blood. 2010;115: 4478-4487.
18. Dimopoulos M, Siegel DS, Lonial S, et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol. 2013;14: 1129-1140.
19. Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci U S A. 2004;101: 540-545.
20. Hui KF, Lam BH, Ho DN, Tsao SW, Chiang AK. Bortezomib and SAHA synergistically induce ROS-driven caspase-dependent apoptosis of nasopharyngeal carcinoma and block replication of Epstein-Barr virus. Mol Cancer Ther. 2013;12: 747-758.
21. Nawrocki ST, Carew JS, Pino MS, et al. Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells. Cancer Res. 2006;66: 3773-3781.
22. Lee JK, Ryu JK, Yang KY, et al. Effects and mechanisms of the combination of suberoylanilide hydroxamic acid and bortezomib on the anticancer property of gemcitabine in pancreatic cancer. Pancreas. 2011;40: 966-973.
23. Sato A, Asano T, Ito K, Asano T. Vorinostat and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells. J Urol. 2012;188: 2410-2418.
24. Sato A, Asano T, Ito K, Sumitomo M, Asano T. Suberoylanilide hydroxamic acid (SAHA) combined with bortezomib inhibits renal cancer growth by enhancing histone acetylation and protein ubiquitination synergistically. BJU Int. 2012;109: 1258-1268.
25. Muscal JA, Thompson PA, Horton TM, et al. A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: a Children's Oncology Group phase I consortium study (ADVL0916). Pediatr Blood Cancer. 2013;60: 390-395.
26. Deming DA, Ninan J, Bailey HH, et al. A Phase I study of intermittently dosed vorinostat in combination with bortezomib in patients with advanced solid tumors. Invest New Drugs. 2014;32: 323-329.
27. Schelman WR, Traynor AM, Holen KD, et al. A phase I study of vorinostat in combination with bortezomib in patients with advanced malignancies. Invest New Drugs. 2013;31: 1539-1546.
28. Millward M, Price T, Townsend A, et al. Phase 1 clinical trial of the novel proteasome inhibitor marizomib with the histone deacetylase inhibitor vorinostat in patients with melanoma, pancreatic and lung cancer based on in vitro assessments of the combination. Invest New Drugs. 2012;30: 2303-2317.