The compound curcumin reactivates the Epstein-Barr virus, offering a safer cancer therapy

A recent study reveals how C210, a curcumin derivative, selectively reactivates the Epstein-Barr virus to kill cancer cells without the risk of infection, paving the way for safer, targeted cancer therapies.

Study: Curcumin derivative C210 induces the Epstein-Barr virus lytic cycle and inhibits virion production by interfering with Hsp90 function. Photo credit: Stephanie Frey / Shutterstock

Study published in the journal Scientific reports identifies a novel curcumin derivative that can effectively induce the Epstein-Barr virus (EBV) lytic cycle by interfering with heat shock protein 90 (HSP90).

Background

Epstein-Barr virus (EBV) is a cancer virus associated with several types of cancer, including epithelial cancers and lymphomas. The virus persists in tumor cells in a latent state, and reactivation of the virus from a latent state to a lytic state leads to the death of the tumor cell.

Lytic induction therapy has been developed to selectively kill EBV-positive tumor cells by inducing viral reactivation using histone deacetylase inhibitors, DNA methyltransferase inhibitors, proteasome inhibitors, and other chemicals. However, the main disadvantages of this therapy are the relatively low efficiency of viral reactivation and the possibility of producing infectious virions, which can then cause viral diseases or promote oncogenesis.

Curcumin, a plant-derived polyphenol, is capable of inducing the unfolded protein response (UPR) and triggering the EBV lytic cycle in cancer cells. The UPR is a cellular stress response activated upon the accumulation of unfolded proteins in the endoplasmic reticulum (ER).

Heat shock protein 90 (HSP90) is a molecular chaperone that promotes proper folding and stability of several oncogenic proteins. Diminutive molecule HSP90 inhibitors induce proteasomal or autophagic degradation of HSP90 client proteins and exert anticancer effects.

In this study, researchers investigated the effect and mode of action of a curcumin derivative, C210 (HSP90 inhibitor), on EBV lytic induction and infectious virion production in EBV-positive nasopharyngeal and gastric carcinoma cell lines.

To investigate the mode of action of C210, they used a conventional lytic inducer, suberoylanilide hydroxamic acid (SAHA; a histone deacetylase inhibitor).

Critical observations

The study showed that the curcumin derivative C210 significantly increased the levels of RNA and proteins associated with the EBV lytic cycle in cancer cells, without inducing the production of infectious virions. To investigate the mode of action of C210, researchers performed HSP90 knockdown experiments and found the induction of lytic RNAs and proteins along with a C210-mediated reduction in EBV lytic activation, indicating that C210 reactivates EBV from its latent state by inhibiting HSP90.

The researchers also observed that C210 interferes with the binding of HSP90 to client proteins, signal transducer and activator of transcription 3 (STAT3) and xeroderma pigmentosum group B complementing protein (XPB), resulting in proteasomal degradation of these proteins. C210-induced degradation and depletion of STAT3 levels resulted in a 2-fold induction of lytic RNA. The researchers suggest that other HSP90 client proteins may also be involved in EBV lytic induction, expanding the range of potential therapeutic targets.

They further observed that C210-induced STAT3 degradation increased the cytotoxic activity and ability of SAHA to reactivate EBV, a combined effect resembling the results of STAT3 knockdown. As for another client protein, HSP90, the researchers found that C210-induced XPB degradation inhibited the expression of SM-dependent overdue viral genes, thereby inhibiting the production of infectious virion.

SM is an early-phase viral regulatory protein that increases the expression of several overdue genes indispensable for viral infectivity. Existing evidence suggests that SM interacts with XPB to recruit it to SM target promoters to specifically induce genes associated with virion assembly and infectivity.

In addition to inhibiting HSP90 and inducing the EBV lytic cycle, C210 also activates the splicing of X-box binding protein 1 (XBP1), which then induces the EBV lytic cycle. XBP1s is an lively transcription factor that binds to and transactivates the ZII region of the EBV BZLF1 promoter to initiate the latent-to-lytic transition.

Conventional lytic inducers such as histone deacetylase inhibitors are known to induce the EBV lytic cycle by promoting histone acetylation. However, the study results show that C210 activates the EBV lytic cycle by inhibiting HSP90 function and increasing XBP1 levels, two mechanisms that differ from established histone deacetylase inhibitors such as SAHA.

Importance of the study

The study identified a recent curcumin derivative, C210, that acts as an HSP90 inhibitor targeting the EBV lytic cycle. The findings may assist develop recent lytic induction therapies for the treatment of EBV-infected malignancies.

So far, three lithium-inducing drugs, gemcitabine, valproic acid, and ganciclovir, have shown promising results in clinical trials. This highlights the need for further development and testing of recent clinical lytic inducers.

Moreover, the study shows that C210 enhances the EBV-reactivating and anti-cancer effects of SAHA while eliminating the negative side effect of SAHA, i.e. the production of infectious virions. These findings suggest that C210 and SAHA combination therapy may represent a recent approach to the treatment of EBV-positive cancer. Given the results, the researchers recommend that future preclinical studies investigate the safety and effectiveness of C210 using animal models of EBV-infected tumors.