Piperlongumine inhibits proliferation and oncogenic MYCN expression in chemoresistant metastatic retinoblastoma cells directly and through extracellular vesicles
Ocular retinoblastoma malignancies, which develop into metastatic phenotypes, result in poor prognosis and survival for infant and child patients. To improve the prognosis of metastatic retinoblastoma, it is important to identify novel compounds with less toxic side effects and higher therapeutic ef...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332223003426 |
| _version_ | 1797857681590976512 |
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| author | Cui Shi Kunhui Huang John Soto Renuka Sankaran Vrinda Kalia Onyekwere Onwumere Michael Young Linda Einbond Stephen Redenti |
| author_facet | Cui Shi Kunhui Huang John Soto Renuka Sankaran Vrinda Kalia Onyekwere Onwumere Michael Young Linda Einbond Stephen Redenti |
| author_sort | Cui Shi |
| collection | DOAJ |
| description | Ocular retinoblastoma malignancies, which develop into metastatic phenotypes, result in poor prognosis and survival for infant and child patients. To improve the prognosis of metastatic retinoblastoma, it is important to identify novel compounds with less toxic side effects and higher therapeutic efficacy compared to existing chemotherapeutics. Piperlongumine (PL), a neuroprotective, plant-derived compound has been explored for its anticancer activities both in vitro and in vivo. Here, we analyze the potential efficacy of PL for metastatic retinoblastoma cell treatment. Our data reveal that PL treatment significantly inhibits cell proliferation in metastatic retinoblastoma Y79 cells compared to the commonly used retinoblastoma chemotherapeutic drugs carboplatin, etoposide, and vincristine. PL treatment also significantly increases cell death compared to treatment with other chemotherapeutic drugs. PL-induced cell-death signaling was associated with significantly higher caspase 3/7 activities and greater loss of mitochondrial membrane potential. PL was also internalized into Y79 cells with an estimated concentration of 0.310pM and expression analysis revealed reduced MYCN oncogene levels. We next examined extracellular vesicles derived from PL-treated Y79 cells. Extracellular vesicles in other cancers are pro-oncogenic, mediating systemic toxicities via the encapsulation of chemotherapeutic drugs. Within metastatic Y79 EV samples, an estimated PL concentration of 0.026pM was detected. PL treatment significantly downregulated Y79 EV cargo of the oncogene MYCN transcript. Interestingly, non-PL-treated Y79 cells incubated with EVs from PL-treated cells exhibited significantly reduced cell growth. These findings indicate that in metastatic Y79 cells, PL exhibits potent anti-proliferation effects and oncogene downregulation. Importantly, PL is also incorporated into extracellular vesicles released from treated metastatic cells with measurable anti-cancer effects on target cells at a distance from the site of primary treatment. The use of PL in the treatment of metastatic retinoblastoma may reduce primary tumor proliferation and inhibit metastatic cancer activity systemically via extracellular vesicle circulation. |
| first_indexed | 2024-04-09T21:00:43Z |
| format | Article |
| id | doaj.art-55a418bc76f743418b24874c1a2c0719 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-09T21:00:43Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-55a418bc76f743418b24874c1a2c07192023-03-29T09:24:21ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-05-01161114554Piperlongumine inhibits proliferation and oncogenic MYCN expression in chemoresistant metastatic retinoblastoma cells directly and through extracellular vesiclesCui Shi0Kunhui Huang1John Soto2Renuka Sankaran3Vrinda Kalia4Onyekwere Onwumere5Michael Young6Linda Einbond7Stephen Redenti8Lehman College, the City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA; Biochemistry Doctoral Program, The Graduate School, City University of New York, 365 Fifth Avenue, New York, NY 10016, USALehman College, the City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA; Biochemistry Doctoral Program, The Graduate School, City University of New York, 365 Fifth Avenue, New York, NY 10016, USALehman College, the City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USALehman College, the City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA; Biochemistry Doctoral Program, The Graduate School, City University of New York, 365 Fifth Avenue, New York, NY 10016, USADepartment of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY 10032, USALehman College, the City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA; Biology Doctoral Program, The Graduate School of the City University of New York, 365 5th Avenue, New York, NY 10016, USAThe Schepens Eye Research Institute, Massachusetts Eye and Ear, Harvard Medical School, 20 Staniford Street, Boston, MA 02114, USALehman College, the City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USALehman College, the City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA; Biochemistry Doctoral Program, The Graduate School, City University of New York, 365 Fifth Avenue, New York, NY 10016, USA; Biology Doctoral Program, The Graduate School of the City University of New York, 365 5th Avenue, New York, NY 10016, USA; Corresponding author at: Lehman College, the City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, USA.Ocular retinoblastoma malignancies, which develop into metastatic phenotypes, result in poor prognosis and survival for infant and child patients. To improve the prognosis of metastatic retinoblastoma, it is important to identify novel compounds with less toxic side effects and higher therapeutic efficacy compared to existing chemotherapeutics. Piperlongumine (PL), a neuroprotective, plant-derived compound has been explored for its anticancer activities both in vitro and in vivo. Here, we analyze the potential efficacy of PL for metastatic retinoblastoma cell treatment. Our data reveal that PL treatment significantly inhibits cell proliferation in metastatic retinoblastoma Y79 cells compared to the commonly used retinoblastoma chemotherapeutic drugs carboplatin, etoposide, and vincristine. PL treatment also significantly increases cell death compared to treatment with other chemotherapeutic drugs. PL-induced cell-death signaling was associated with significantly higher caspase 3/7 activities and greater loss of mitochondrial membrane potential. PL was also internalized into Y79 cells with an estimated concentration of 0.310pM and expression analysis revealed reduced MYCN oncogene levels. We next examined extracellular vesicles derived from PL-treated Y79 cells. Extracellular vesicles in other cancers are pro-oncogenic, mediating systemic toxicities via the encapsulation of chemotherapeutic drugs. Within metastatic Y79 EV samples, an estimated PL concentration of 0.026pM was detected. PL treatment significantly downregulated Y79 EV cargo of the oncogene MYCN transcript. Interestingly, non-PL-treated Y79 cells incubated with EVs from PL-treated cells exhibited significantly reduced cell growth. These findings indicate that in metastatic Y79 cells, PL exhibits potent anti-proliferation effects and oncogene downregulation. Importantly, PL is also incorporated into extracellular vesicles released from treated metastatic cells with measurable anti-cancer effects on target cells at a distance from the site of primary treatment. The use of PL in the treatment of metastatic retinoblastoma may reduce primary tumor proliferation and inhibit metastatic cancer activity systemically via extracellular vesicle circulation.http://www.sciencedirect.com/science/article/pii/S0753332223003426Metastatic retinoblastomaPiperlongumineExtracellular vesiclesChemotherapeutic drugsChemoresistanceMYCN |
| spellingShingle | Cui Shi Kunhui Huang John Soto Renuka Sankaran Vrinda Kalia Onyekwere Onwumere Michael Young Linda Einbond Stephen Redenti Piperlongumine inhibits proliferation and oncogenic MYCN expression in chemoresistant metastatic retinoblastoma cells directly and through extracellular vesicles Biomedicine & Pharmacotherapy Metastatic retinoblastoma Piperlongumine Extracellular vesicles Chemotherapeutic drugs Chemoresistance MYCN |
| title | Piperlongumine inhibits proliferation and oncogenic MYCN expression in chemoresistant metastatic retinoblastoma cells directly and through extracellular vesicles |
| title_full | Piperlongumine inhibits proliferation and oncogenic MYCN expression in chemoresistant metastatic retinoblastoma cells directly and through extracellular vesicles |
| title_fullStr | Piperlongumine inhibits proliferation and oncogenic MYCN expression in chemoresistant metastatic retinoblastoma cells directly and through extracellular vesicles |
| title_full_unstemmed | Piperlongumine inhibits proliferation and oncogenic MYCN expression in chemoresistant metastatic retinoblastoma cells directly and through extracellular vesicles |
| title_short | Piperlongumine inhibits proliferation and oncogenic MYCN expression in chemoresistant metastatic retinoblastoma cells directly and through extracellular vesicles |
| title_sort | piperlongumine inhibits proliferation and oncogenic mycn expression in chemoresistant metastatic retinoblastoma cells directly and through extracellular vesicles |
| topic | Metastatic retinoblastoma Piperlongumine Extracellular vesicles Chemotherapeutic drugs Chemoresistance MYCN |
| url | http://www.sciencedirect.com/science/article/pii/S0753332223003426 |
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