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Curcumin Compound Reactivates Epstein–Barr Virus, Offering Safer Cancer Therapy
A new study reveals how C210, a curcumin derivative, selectively reactivates Epstein–Barr virus to kill cancer cells without infectious risks, paving the way for safer, targeted cancer therapies.
Study: Curcumin derivative C210 induces Epstein–Barr virus lytic cycle and inhibits virion production by disrupting Hsp90 function. Image Credit: Stephanie Frey / Shutterstock
A study published in the journal Scientific Reports identifies a novel curcumin derivative that can effectively induce the Epstein–Barr virus (EBV) lytic cycle by disrupting heat shock protein 90 (HSP90).
BackgroundEpstein–Barr virus (EBV) is a tumorigenic virus associated with a range of cancer types, including epithelial cancers and lymphomas. The virus persists in cancer cells in a latent state, and viral reactivation from the latent state to the lytic state leads to cancer cell death.
Lytic induction therapy has been developed to selectively kill EBV-positive cancer cells by triggering viral reactivation using histone deacetylase inhibitors, DNA methyltransferase inhibitors, proteasome inhibitors, and other chemical compounds. However, the major drawbacks of this therapy are relatively low viral reactivation efficacy and the possibility of producing infectious virions that can subsequently trigger 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 the proper folding and stability of several oncogenic proteins. Small-molecule inhibitors of HSP90 trigger proteasomal or autophagic degradation of HSP90 client proteins and exert antitumor effects.
In this study, scientists have investigated the effect and mode of action of a curcumin derivative, C210 (an HSP90 inhibitor), on EBV lytic induction and infectious virion production in EBV-positive nasopharyngeal carcinoma and gastric carcinoma cell lines.
They have used a conventional lytic inducer, suberoylanilide hydroxamic acid (SAHA; a histone deacetylase inhibitor), to investigate the mode of action of C210.
Important ObservationsThe study found that the curcumin derivative C210 significantly upregulates RNAs and proteins associated with the EBV lytic cycle in cancer cells without inducing the production of infectious virions. To investigate C210's mode of action, scientists performed HSP90 knockdown experiments and found an induction in lytic RNAs and proteins alongside a reduction in C210-mediated EBV lytic activation, indicating that C210 reactivates EBV from its latent state by inhibiting HSP90.
The scientists also observed that C210 disrupts the binding of HSP90 to its client proteins, signal transducer and activator of transcription 3 (STAT3), and xeroderma pigmentosum group B-complementing protein (XPB), resulting in the proteasomal degradation of these proteins. The C210-induced degradation and depletion of STAT3 levels caused a 2-fold induction in lytic RNA. Scientists suggest that other HSP90 client proteins may also be involved in EBV lytic induction, broadening the scope for potential therapeutic targets.
They further observed that C210-induced STAT3 degradation enhanced the cytotoxic activity and EBV-reactivating capacity of SAHA, a combination effect that resembled STAT3 knockdown results. Regarding the other HSP90 client protein, scientists found that C210-induced degradation of XPB inhibits the expression of SM-dependent late viral genes, thereby suppressing infectious virion production.
SM is an early-phase regulatory viral protein that increases the expression of several late genes required for viral infectivity. Existing evidence suggests that SM interacts with XPB, recruiting it to SM target promoters to specifically induce genes related to virion assembly and infectivity.
Besides inhibiting HSP90 and inducing the EBV lytic cycle, C210 also activates X box binding protein 1 splicing (XBP1s), which then induces the EBV lytic cycle. XBP1s is an active transcription factor that binds to and transactivates the ZII region of the EBV BZLF1 promoter to initiate the latent-to-lytic switch.
Conventional lytic inducers, such as histone deacetylase inhibitors, are known to induce the EBV lytic cycle by promoting histone acetylation. The study findings, however, show that C210 activates the EBV lytic cycle by inhibiting HSP90 function and upregulating XBP1s, two mechanisms that differ from those of established histone deacetylase inhibitors like SAHA.
Study SignificanceThe study identifies a new curcumin derivative, C210, that acts as an HSP90 inhibitor targeting the EBV lytic cycle. The findings could support the development of novel lytic induction therapies to treat EBV-positive malignancies.
So far, three lytic-inducing drugs, gemcitabine, valproic acid, and ganciclovir, have shown promising outcomes in clinical trials. This emphasizes the need to continue developing and testing new clinical lytic inducers.
Moreover, the study shows that C210 enhances the EBV-reactivating and antitumor effects of SAHA while eliminating SAHA's negative side effect, infectious virion production. These findings suggest that combination therapy of C210 and SAHA may represent a new approach for EBV-positive cancer treatments. Given the results, the scientists recommend that future preclinical trials investigate C210's safety and efficacy using animal models of EBV-infected tumors.
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Nutritional Supplements With Curcumin Could Curb Macular Degeneration, Study Suggests
1 of 2Although no treatments exist to reverse macular degeneration, researchers say some dietary supplements can help prevent the condition from becoming worse. Photo by Ksenia Chernaya/Pexels
NEW YORK, Oct. 24 (UPI) -- Nutritional supplements that contain curcumin -- a natural anti-inflammatory compound -- may protect the eyes from the development and progression of age-related macular degeneration, a new study suggests.
The study was published Thursday in JAMA Ophthalmology.
Macular degeneration is the most frequent cause of irreversible vision loss in the developed world. It affects the macula -- the center of the light-sensitive retina at the back of the eye -- and can cause in blurred vision or a blind spot primarily in people older than 50.
Although no treatments exist to reverse macular degeneration, researchers say some dietary supplements can help prevent the condition from becoming worse.
"Curcumin is the biologically active ingredient of turmeric," the golden-orange spice used to flavor foods, the study's corresponding author, Dr. Ehsan Rahimy, an ophthalmologist and adjunct clinical assistant professor in the Byers Eye Institute at Stanford Medicine in Palo Alto, Calif., told UPI.
"We see it promoted as a health supplement in many circles of medicine," Rahimy said.
In addition to anti-inflammatory effects, the supplement has antioxidant properties, which help shield cells from damage, aging and eventually death, he noted.
While research suggests that genetics, age and smoking play a role in this condition, emerging evidence indicates that "chronic inflammation in the body can contribute to macular degeneration formation and progression," Rahimy said.
Curcumin comes from the Curcuma longa plant's root and is used in curry dishes and as a remedy for different afflictions throughout South Asia, according to the study.
To conduct the investigation, researchers compared patients taking curcuma supplements to those who were not. All patients were at least 50 years old and did not have a history of macular degeneration at the study's start.
The results showed that taking curcuma supplements was associated with a 77% lower risk of developing dry macular degeneration -- the most common type. People with a less common type -- wet macular degeneration -- had a 72% reduced risk of developing the condition.
Among patients who took supplements compared with patients who did not, the results showed a 54% decreased risk of blindness and an 85% lower risk of needing anti-vascular injections into the eye to manage the macular degeneration.
Researchers said they found the results to remain consistent among patients 60 and 70 years old or older.
They collected data from an electronic health records research network in Cambridge, Mass.
This review included 66,804 patients -- 65% female, with an average age of 65 -- who took prescribed, curcuma-based supplements. For comparison, they included 1,809,440 patients -- 55% female, with an average age of 67 -- who did not take such prescribed supplements.
When researchers performed additional matching to balance various patient characteristics, this led to further analysis of 66,799 individuals in each group.
"We can gather a lot of unique, real-world insights from studying such large numbers of patients," Rahimy said. "You're seeing the forest and not really the trees, and we're basically looking for interesting trends."
However, he cautioned that while this research does not prove cause and effect, "it helps support some of the existing studies and literature on this topic, and at the same time, it should hopefully help stimulate or inspire new studies."
Dr. Flora Lum, clinical spokesperson for the American Academy of Ophthalmology, told UPI that "this is not the type of study that can show the supplements slowed the worsening of age-related macular degeneration -- it suggests an association only." She was not involved in conducting the research.
"More study is needed to validate these findings," Flum said, voicing concern that the database from which researchers extracted information consists of large institutions. Patients diagnosed with age-related macular degeneration or in more advanced stages may have gone outside this network, she said.
However, "it is the first time a large-scale study like this has been performed looking at association of curcumin and risk of developing age-related macular degeneration and its progression," said Dr. Swetangi Bhaleeya, an associate professor and director of the retina and uveitis service at the University of South Florida in Tampa.
Even so, the study does not specify which dose or formulation of curcumin patients took and other confounding factors that could have played a role in modifying the risk of disease.
Dr. Judy Kim, a professor of ophthalmology at UT Southwestern Medical Center in Dallas, said with the world's increasingly older population, "slowing down or preventing diseases that cause blindness due to aging processes will be important."
Kim recommends an anti-inflammatory and antioxidant diet, along with exercise and abstinence from smoking, especially for patients who are at high risk for age-related macular degeneration or have an early stage of the disease.
"Healthy lifestyle will aid in healthy sight," she said.
Can Curcumin And Quercetin Regress Polyps In Patients With FAP?
Cite this articleCan curcumin and quercetin regress polyps in patients with FAP?. Nat Rev Gastroenterol Hepatol 3, 604 (2006). Https://doi.Org/10.1038/ncpgasthep0623
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