Curcuminoids as EBV lytic activators for adjuvant treatment in EBV-positive carcinomas

Octavia Ramayanti, Mitch Brinkkemper, Sandra A. W. M. Verkuijlen, Leni Ritmaleni, Mei Lin Go, Jaap M. Middeldorp

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Epstein-Barr virus (EBV) persists in nasopharyngeal (NPC) and gastric carcinomas (EBVaGC) in a tightly latent form. Cytolytic virus activation (CLVA) therapy employs gemcitabine and valproic acid (GCb+VPA) to reactivate latent EBV into the lytic phase and antiviral valganciclovir to enhance cell death and prevent virus production. CLVA treatment has proven safe in phase-I/II trials with promising clinical responses in patients with recurrent NPC. However, a major challenge is to maximize EBV lytic reactivation by CLVA. Curcumin, a dietary spice used in Asian countries, is known for its antitumor property and therapeutic potential. Novel curcuminoids that were developed to increase efficacy and bioavailability may serve as oral CLVA adjuvants. We investigated the potential of curcumin and its analogs (curcuminoids) to trigger the EBV lytic cycle in EBVaGC and NPC cells. EBV-reactivating effects were measured by immunoblot and immunofluorescence using monoclonal antibodies specific for EBV lytic proteins. Two of the hit compounds (41, EF24) with high lytic inducing activity were further studied for their synergistic or antagonistic effects when combined with GCb+VPA and analyzed by cytotoxicity and mRNA profiling assays to measure the EBV reactivation. Curcuminoid as a single agent significantly induced EBV reactivation in recombinant GC and NPC lines. The drug effects were dose- and time-dependent. Micromolar concentration of curcuminoid EF24 enhanced the CLVA effect in all cell systems except SNU719, a naturally infected EBVaGC cell that carries a more tightly latent viral genome. These findings indicated that EF24 has potential as EBV lytic activator and may serve as an adjuvant in CLVA treatment.
Original languageEnglish
Article number89
JournalCancers
Volume10
Issue number4
DOIs
Publication statusPublished - 2018

Cite this

Ramayanti, O., Brinkkemper, M., Verkuijlen, S. A. W. M., Ritmaleni, L., Go, M. L., & Middeldorp, J. M. (2018). Curcuminoids as EBV lytic activators for adjuvant treatment in EBV-positive carcinomas. Cancers, 10(4), [89]. https://doi.org/10.3390/cancers10040089
Ramayanti, Octavia ; Brinkkemper, Mitch ; Verkuijlen, Sandra A. W. M. ; Ritmaleni, Leni ; Go, Mei Lin ; Middeldorp, Jaap M. / Curcuminoids as EBV lytic activators for adjuvant treatment in EBV-positive carcinomas. In: Cancers. 2018 ; Vol. 10, No. 4.
@article{e0669b6f391743ad8e9b5235d3ed2ac4,
title = "Curcuminoids as EBV lytic activators for adjuvant treatment in EBV-positive carcinomas",
abstract = "Epstein-Barr virus (EBV) persists in nasopharyngeal (NPC) and gastric carcinomas (EBVaGC) in a tightly latent form. Cytolytic virus activation (CLVA) therapy employs gemcitabine and valproic acid (GCb+VPA) to reactivate latent EBV into the lytic phase and antiviral valganciclovir to enhance cell death and prevent virus production. CLVA treatment has proven safe in phase-I/II trials with promising clinical responses in patients with recurrent NPC. However, a major challenge is to maximize EBV lytic reactivation by CLVA. Curcumin, a dietary spice used in Asian countries, is known for its antitumor property and therapeutic potential. Novel curcuminoids that were developed to increase efficacy and bioavailability may serve as oral CLVA adjuvants. We investigated the potential of curcumin and its analogs (curcuminoids) to trigger the EBV lytic cycle in EBVaGC and NPC cells. EBV-reactivating effects were measured by immunoblot and immunofluorescence using monoclonal antibodies specific for EBV lytic proteins. Two of the hit compounds (41, EF24) with high lytic inducing activity were further studied for their synergistic or antagonistic effects when combined with GCb+VPA and analyzed by cytotoxicity and mRNA profiling assays to measure the EBV reactivation. Curcuminoid as a single agent significantly induced EBV reactivation in recombinant GC and NPC lines. The drug effects were dose- and time-dependent. Micromolar concentration of curcuminoid EF24 enhanced the CLVA effect in all cell systems except SNU719, a naturally infected EBVaGC cell that carries a more tightly latent viral genome. These findings indicated that EF24 has potential as EBV lytic activator and may serve as an adjuvant in CLVA treatment.",
author = "Octavia Ramayanti and Mitch Brinkkemper and Verkuijlen, {Sandra A. W. M.} and Leni Ritmaleni and Go, {Mei Lin} and Middeldorp, {Jaap M.}",
year = "2018",
doi = "10.3390/cancers10040089",
language = "English",
volume = "10",
journal = "Cancers (Basel)",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "4",

}

Ramayanti, O, Brinkkemper, M, Verkuijlen, SAWM, Ritmaleni, L, Go, ML & Middeldorp, JM 2018, 'Curcuminoids as EBV lytic activators for adjuvant treatment in EBV-positive carcinomas' Cancers, vol. 10, no. 4, 89. https://doi.org/10.3390/cancers10040089

Curcuminoids as EBV lytic activators for adjuvant treatment in EBV-positive carcinomas. / Ramayanti, Octavia; Brinkkemper, Mitch; Verkuijlen, Sandra A. W. M.; Ritmaleni, Leni; Go, Mei Lin; Middeldorp, Jaap M.

In: Cancers, Vol. 10, No. 4, 89, 2018.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Curcuminoids as EBV lytic activators for adjuvant treatment in EBV-positive carcinomas

AU - Ramayanti, Octavia

AU - Brinkkemper, Mitch

AU - Verkuijlen, Sandra A. W. M.

AU - Ritmaleni, Leni

AU - Go, Mei Lin

AU - Middeldorp, Jaap M.

PY - 2018

Y1 - 2018

N2 - Epstein-Barr virus (EBV) persists in nasopharyngeal (NPC) and gastric carcinomas (EBVaGC) in a tightly latent form. Cytolytic virus activation (CLVA) therapy employs gemcitabine and valproic acid (GCb+VPA) to reactivate latent EBV into the lytic phase and antiviral valganciclovir to enhance cell death and prevent virus production. CLVA treatment has proven safe in phase-I/II trials with promising clinical responses in patients with recurrent NPC. However, a major challenge is to maximize EBV lytic reactivation by CLVA. Curcumin, a dietary spice used in Asian countries, is known for its antitumor property and therapeutic potential. Novel curcuminoids that were developed to increase efficacy and bioavailability may serve as oral CLVA adjuvants. We investigated the potential of curcumin and its analogs (curcuminoids) to trigger the EBV lytic cycle in EBVaGC and NPC cells. EBV-reactivating effects were measured by immunoblot and immunofluorescence using monoclonal antibodies specific for EBV lytic proteins. Two of the hit compounds (41, EF24) with high lytic inducing activity were further studied for their synergistic or antagonistic effects when combined with GCb+VPA and analyzed by cytotoxicity and mRNA profiling assays to measure the EBV reactivation. Curcuminoid as a single agent significantly induced EBV reactivation in recombinant GC and NPC lines. The drug effects were dose- and time-dependent. Micromolar concentration of curcuminoid EF24 enhanced the CLVA effect in all cell systems except SNU719, a naturally infected EBVaGC cell that carries a more tightly latent viral genome. These findings indicated that EF24 has potential as EBV lytic activator and may serve as an adjuvant in CLVA treatment.

AB - Epstein-Barr virus (EBV) persists in nasopharyngeal (NPC) and gastric carcinomas (EBVaGC) in a tightly latent form. Cytolytic virus activation (CLVA) therapy employs gemcitabine and valproic acid (GCb+VPA) to reactivate latent EBV into the lytic phase and antiviral valganciclovir to enhance cell death and prevent virus production. CLVA treatment has proven safe in phase-I/II trials with promising clinical responses in patients with recurrent NPC. However, a major challenge is to maximize EBV lytic reactivation by CLVA. Curcumin, a dietary spice used in Asian countries, is known for its antitumor property and therapeutic potential. Novel curcuminoids that were developed to increase efficacy and bioavailability may serve as oral CLVA adjuvants. We investigated the potential of curcumin and its analogs (curcuminoids) to trigger the EBV lytic cycle in EBVaGC and NPC cells. EBV-reactivating effects were measured by immunoblot and immunofluorescence using monoclonal antibodies specific for EBV lytic proteins. Two of the hit compounds (41, EF24) with high lytic inducing activity were further studied for their synergistic or antagonistic effects when combined with GCb+VPA and analyzed by cytotoxicity and mRNA profiling assays to measure the EBV reactivation. Curcuminoid as a single agent significantly induced EBV reactivation in recombinant GC and NPC lines. The drug effects were dose- and time-dependent. Micromolar concentration of curcuminoid EF24 enhanced the CLVA effect in all cell systems except SNU719, a naturally infected EBVaGC cell that carries a more tightly latent viral genome. These findings indicated that EF24 has potential as EBV lytic activator and may serve as an adjuvant in CLVA treatment.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85045328775&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/29565326

U2 - 10.3390/cancers10040089

DO - 10.3390/cancers10040089

M3 - Article

VL - 10

JO - Cancers (Basel)

JF - Cancers (Basel)

SN - 2072-6694

IS - 4

M1 - 89

ER -