Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization
Abstract Target therapies based on BRAF and MEK inhibitors (MAPKi) have changed the therapeutic landscape for metastatic melanoma patients bearing mutations in the BRAF kinase. However, the emergence of drug resistance imposes the necessity to conceive novel therapeutic strategies capable to achieve...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-09-01
|
| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12964-020-00633-7 |
| _version_ | 1828403206186598400 |
|---|---|
| author | Luigi Fattore Debora Malpicci Ciro Milite Sabrina Castellano Gianluca Sbardella Gerardo Botti Paolo A. Ascierto Rita Mancini Gennaro Ciliberto |
| author_facet | Luigi Fattore Debora Malpicci Ciro Milite Sabrina Castellano Gianluca Sbardella Gerardo Botti Paolo A. Ascierto Rita Mancini Gennaro Ciliberto |
| author_sort | Luigi Fattore |
| collection | DOAJ |
| description | Abstract Target therapies based on BRAF and MEK inhibitors (MAPKi) have changed the therapeutic landscape for metastatic melanoma patients bearing mutations in the BRAF kinase. However, the emergence of drug resistance imposes the necessity to conceive novel therapeutic strategies capable to achieve a more durable disease control. In the last years, retrotransposons laying in human genome have been shown to undergo activation during tumorigenesis, where they contribute to genomic instability. Their activation can be efficiently controlled with reverse transcriptase inhibitors (RTIs) frequently used in the treatment of AIDS. These drugs have demonstrated anti-proliferative effects in several cancer models, including also metastatic melanoma. However, to our knowledge no previous study investigated the capability of RTIs to mitigate drug resistance to target therapy in BRAF-mutant melanomas. In this short report we show that the non-nucleoside RTI, SPV122 in combination with MAPKi strongly inhibits BRAF-mutant melanoma cell growth, induces apoptosis, and delays the emergence of resistance to target therapy in vitro. Mechanistically, this combination strongly induces DNA double-strand breaks, mitochondrial membrane depolarization and increased ROS levels. Our results shed further light on the molecular activity of RTI in melanoma and pave the way to their use as a novel therapeutic option to improve the efficacy of target therapy. Video Abstract Graphical abstract |
| first_indexed | 2024-12-10T10:14:06Z |
| format | Article |
| id | doaj.art-8baf532c4e794078a353eee3b5000985 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-12-10T10:14:06Z |
| publishDate | 2020-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-8baf532c4e794078a353eee3b50009852022-12-22T01:53:03ZengBMCCell Communication and Signaling1478-811X2020-09-011811910.1186/s12964-020-00633-7Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarizationLuigi Fattore0Debora Malpicci1Ciro Milite2Sabrina Castellano3Gianluca Sbardella4Gerardo Botti5Paolo A. Ascierto6Rita Mancini7Gennaro Ciliberto8Istituto Nazionale Tumori IRCCS, “Fondazione G. Pascale”Department of Experimental and Clinical Medicine, University “Magna Graecia” of CatanzaroDepartment of Pharmacy, Epigenetic Med Chem Lab, University of SalernoDepartment of Pharmacy, Epigenetic Med Chem Lab, University of SalernoDepartment of Pharmacy, Epigenetic Med Chem Lab, University of SalernoIstituto Nazionale Tumori IRCCS, “Fondazione G. Pascale”Istituto Nazionale Tumori IRCCS, “Fondazione G. Pascale”Department of Molecular and Clinical Medicine, University of Roma “Sapienza”IRCCS, Istituto Nazionale Tumori “Regina Elena”Abstract Target therapies based on BRAF and MEK inhibitors (MAPKi) have changed the therapeutic landscape for metastatic melanoma patients bearing mutations in the BRAF kinase. However, the emergence of drug resistance imposes the necessity to conceive novel therapeutic strategies capable to achieve a more durable disease control. In the last years, retrotransposons laying in human genome have been shown to undergo activation during tumorigenesis, where they contribute to genomic instability. Their activation can be efficiently controlled with reverse transcriptase inhibitors (RTIs) frequently used in the treatment of AIDS. These drugs have demonstrated anti-proliferative effects in several cancer models, including also metastatic melanoma. However, to our knowledge no previous study investigated the capability of RTIs to mitigate drug resistance to target therapy in BRAF-mutant melanomas. In this short report we show that the non-nucleoside RTI, SPV122 in combination with MAPKi strongly inhibits BRAF-mutant melanoma cell growth, induces apoptosis, and delays the emergence of resistance to target therapy in vitro. Mechanistically, this combination strongly induces DNA double-strand breaks, mitochondrial membrane depolarization and increased ROS levels. Our results shed further light on the molecular activity of RTI in melanoma and pave the way to their use as a novel therapeutic option to improve the efficacy of target therapy. Video Abstract Graphical abstracthttp://link.springer.com/article/10.1186/s12964-020-00633-7MelanomaReverse transcriptase inhibitorsTarget therapyDrug resistanceMitochondrial membrane depolarizationDSBs |
| spellingShingle | Luigi Fattore Debora Malpicci Ciro Milite Sabrina Castellano Gianluca Sbardella Gerardo Botti Paolo A. Ascierto Rita Mancini Gennaro Ciliberto Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization Cell Communication and Signaling Melanoma Reverse transcriptase inhibitors Target therapy Drug resistance Mitochondrial membrane depolarization DSBs |
| title | Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization |
| title_full | Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization |
| title_fullStr | Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization |
| title_full_unstemmed | Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization |
| title_short | Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization |
| title_sort | reverse transcriptase inhibition potentiates target therapy in braf mutant melanomas effects on cell proliferation apoptosis dna damage ros induction and mitochondrial membrane depolarization |
| topic | Melanoma Reverse transcriptase inhibitors Target therapy Drug resistance Mitochondrial membrane depolarization DSBs |
| url | http://link.springer.com/article/10.1186/s12964-020-00633-7 |
| work_keys_str_mv | AT luigifattore reversetranscriptaseinhibitionpotentiatestargettherapyinbrafmutantmelanomaseffectsoncellproliferationapoptosisdnadamagerosinductionandmitochondrialmembranedepolarization AT deboramalpicci reversetranscriptaseinhibitionpotentiatestargettherapyinbrafmutantmelanomaseffectsoncellproliferationapoptosisdnadamagerosinductionandmitochondrialmembranedepolarization AT ciromilite reversetranscriptaseinhibitionpotentiatestargettherapyinbrafmutantmelanomaseffectsoncellproliferationapoptosisdnadamagerosinductionandmitochondrialmembranedepolarization AT sabrinacastellano reversetranscriptaseinhibitionpotentiatestargettherapyinbrafmutantmelanomaseffectsoncellproliferationapoptosisdnadamagerosinductionandmitochondrialmembranedepolarization AT gianlucasbardella reversetranscriptaseinhibitionpotentiatestargettherapyinbrafmutantmelanomaseffectsoncellproliferationapoptosisdnadamagerosinductionandmitochondrialmembranedepolarization AT gerardobotti reversetranscriptaseinhibitionpotentiatestargettherapyinbrafmutantmelanomaseffectsoncellproliferationapoptosisdnadamagerosinductionandmitochondrialmembranedepolarization AT paoloaascierto reversetranscriptaseinhibitionpotentiatestargettherapyinbrafmutantmelanomaseffectsoncellproliferationapoptosisdnadamagerosinductionandmitochondrialmembranedepolarization AT ritamancini reversetranscriptaseinhibitionpotentiatestargettherapyinbrafmutantmelanomaseffectsoncellproliferationapoptosisdnadamagerosinductionandmitochondrialmembranedepolarization AT gennarociliberto reversetranscriptaseinhibitionpotentiatestargettherapyinbrafmutantmelanomaseffectsoncellproliferationapoptosisdnadamagerosinductionandmitochondrialmembranedepolarization |