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Effe ct of combination of bort_romidepsin on tumor growth s uppression of NPC xe

Effe ct of combination of bort_romidepsin on tumor growth s uppression of NPC xe

Effects of SAHA_bortezomib on growth of Wp-restricted BL xenografts established

Effects of SAHA_bortezomib on growth of Wp-restricted BL xenografts established

Effects of caspase-4 inhibition on ROS generation and ER stress activation (a). HA cells were pretreated with either 50uM Z-VAD-FMK, Z-YVAD-FMK, Z-IETD-FMK or Z-LEHD-FMK for 1 hr followed by treatment with combination of 15 nM bortezomib and 5 nM romidepsin or either drug alone for 24 hr. Expression of PARP, cleaved PARP, cleaved caspase-3 and CHOP/GADD153 was detected by western blot analysis.

Effects of caspase-4 inhibition on ROS generation and ER stress activation (b) HA cells were pretreated with either 50uM Z-VAD-FMK or 12mM NAC for 1 hr followed by treatment with bort/romidepsin for 24 hr. Percentages of apoptotic cells were detected by TUNEL staining.

Effects of caspase-4 inhibition on ROS generation and ER stress activation (c) Expression of CHOP/GADD153 (green signals) and cleaved PARP (red signals) in HA cells was detected by immunofluorescent staining. DAPI (blue signals) stained the cell nuclei.

Effects of caspase-4 inhibition on ROS generation and ER stress activation (d) Percentages of cells with increased ROS level were detected by DCFH-DA assay.

Effects of caspase-4 inhibition on ROS generation and ER stress activation (e) The cells after treatment with bort/romidepsin for 48 hr were analyzed for the activaition of caspase 3/cell death by Z-DEVD/propidium iodide staining.

Effects of caspase-4 inhibition on ROS generation and ER stress activation (f) Schematic diagram showing the mechanisms of apoptosis of NPC cells induced by combination of proteasome and class I HDAC inhibitors.

Novel Therapeutic Strategies 

 

In Epstein-Barr virus (EBV)-associated malignancies, the virus is harbored in every tumor cell and persists in tightly latent forms expressing a very limited number of viral latent proteins. Induction of EBV lytic cycle leads to expression of a much larger number of viral proteins, which may serve as potential therapeutic targets.

 

We found that 4 histone deacetylase inhibitors, namely trichostatin A (TSA), sodium butyrate (SB), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA), all significantly induced EBV lytic cycle in EBV-positive gastric carcinoma cells (AGS/BX1, latency II) but only weakly induced in Burkitt lymphoma cells (AK2003, latency I) and did not induce in lymphoblastoid cells (LCLs, latency III). Interestingly, SAHA potently induced viral lytic cycle in AGS/BX1 cells at micromolar concentrations (evidenced by 8-fold increase in viral DNA replication, strong expression of viral lytic proteins and production of infectious virus particles) and mediated enhanced cell death of EBV-positive AGS/BX1 cells when compared with that of EBV-negative AGS cells, possibly related to cell cycle arrest at G2/M phase. Furthermore, SAHA effected strong induction of EBV lytic cycle in nasopharyngeal carcinoma but not in NK lymphoma cells (both expressing EBV latency II pattern), indicating preferential viral lytic induction in epithelial rather than lymphoid malignancies.

 

After concluding that SAHA proves to be a potent EBV lytic cycle inducing agent, the effect of drug combination, such as bortezomib and romidepsin are intensely investigated in vivo and in vitro to develop more effective novel drug therapies. 

Read our recent studies on Novel Therapeutic Strategies: 

 

  1. KF Hui, PL Yeung and AKS Chiang. Induction of MAPK- and ROS-dependent autophagy and apoptosis in gastric carcinoma by combination of romidepsin and bortezomib. Oncotarget, 2015 (in press ; IF : 6.359)

  2. CK Choi, DN Ho, KF Hui, RYT Kao and AKS Chiang. Identification of novel small organic compounds with diverse structures for the induction of Epstein-Barr virus (EBV) lytic cycle in EBV-positive epithelial malignancies. Plos One, 2015 (in press; IF : 3.234)

  3. KF Hui and AKS Chiang. Reactivation of Epstein-Barr virus lytic cycle by histone deacetylase inhibitors. Can Cell Microenviron, doi: 10.14800/ccm.1033, 2015 (Review article; in press)

  4. KF Hui, AK Cheung, CK Choi, PL Yeung, AK Cheung, JM Middeldorp, ML Lung, GSW Tsao and AKS Chiang. Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir. Int J Cancer 138(1):125-36, 2016 (Editor’s Choice; IF : 5.09)

  5. KF Hui, YY Leung, PL Yeung, Jaap Middelorp and AKS Chiang. Combination of SAHA and bortezomib up-regulates CDKN2A and CDKN1A and induces apoptosis of Epstein-Barr virus-positive Wp-restricted Burkitt lymphoma and lymphoblastoid cell lines. Br J Haematol, 167:639-50, 2014 (IF : 4.959)

  6. KF Hui and AKS Chiang. Combination of proteasome and class I HDAC inhibitors induces apoptosis of NPC cells through an HDAC6-independent ER stress-induced mechanism. Int J Cancer 135: 2950-61, 2014 (IF : 6.198)

  7. KF Hui, BHW Lam, Dona N Ho, GSW Tsao and AKS Chiang. Bortezomib and SAHA synergistically induce ROS-driven caspase-dependent apoptosis of nasopharyngeal carcinoma and block replication of Epstein-Barr virus. Mol Cancer Ther. 12:747-58, 2013 (IF: 5.599)

  8. KF Hui, Dona N Ho, CM Tsang, Jaap Middeldorp, GSW Tsao and AKS Chiang. Activation of lytic cycle of Epstein-Barr virus by suberoylanilide hydroxamic acid leads to apoptosis and tumor growth suppression of nasopharyngeal carcinoma. Int J Cancer 131 :1930-40, 2012 (IF: 6.198)

  9. KF Hui and AKS Chiang. Suberoylanilide hydroxamic acid (SAHA) induces viral lytic cycle in Epstein-Barr virus-positive epithelial malignancies and mediates enhanced cell death. Int J Cancer 126: 2479-2489, 2010 (IF: 6.198)

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