Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment
To find new anti-cancer drug therapies, we wanted to exploit homeostatic vulnerabilities within Tuberous Sclerosis Complex 2 (TSC2)-deficient cells with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivity. We show that nelfinavir and mefloquine synergize to selectively evoke a cytotoxic...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2018-10-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | http://www.mdpi.com/2072-6694/10/10/375 |
| _version_ | 1797726706247663616 |
|---|---|
| author | Henry D. McCann Charlotte E. Johnson Rachel J. Errington D. Mark Davies Elaine A. Dunlop Andrew R. Tee |
| author_facet | Henry D. McCann Charlotte E. Johnson Rachel J. Errington D. Mark Davies Elaine A. Dunlop Andrew R. Tee |
| author_sort | Henry D. McCann |
| collection | DOAJ |
| description | To find new anti-cancer drug therapies, we wanted to exploit homeostatic vulnerabilities within Tuberous Sclerosis Complex 2 (TSC2)-deficient cells with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivity. We show that nelfinavir and mefloquine synergize to selectively evoke a cytotoxic response in TSC2-deficient cell lines with mTORC1 hyperactivity. We optimize the concentrations of nelfinavir and mefloquine to a clinically viable range that kill cells that lack TSC2, while wild-type cells tolerate treatment. This new clinically viable drug combination causes a significant level of cell death in TSC2-deficient tumor spheroids. Furthermore, no cell recovery was apparent after drug withdrawal, revealing potent cytotoxicity. Transcriptional profiling by RNA sequencing of drug treated TSC2-deficient cells compared to wild-type cells suggested the cytotoxic mechanism of action, involving initial ER stress and an imbalance in energy homeostatic pathways. Further characterization revealed that supplementation with methyl pyruvate alleviated energy stress and reduced the cytotoxic effect, implicating energy deprivation as the trigger of cell death. This work underpins a critical vulnerability with cancer cells with aberrant signaling through the TSC2-mTORC1 pathway that lack flexibility in homeostatic pathways, which could be exploited with combined nelfinavir and mefloquine treatment. |
| first_indexed | 2024-03-12T10:49:11Z |
| format | Article |
| id | doaj.art-05b44a71a37043bcb028a1fc33b65b81 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T10:49:11Z |
| publishDate | 2018-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-05b44a71a37043bcb028a1fc33b65b812023-09-02T07:08:53ZengMDPI AGCancers2072-66942018-10-01101037510.3390/cancers10100375cancers10100375Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine TreatmentHenry D. McCann0Charlotte E. Johnson1Rachel J. Errington2D. Mark Davies3Elaine A. Dunlop4Andrew R. Tee5Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKDivision of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKDivision of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKDivision of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKDivision of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKDivision of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UKTo find new anti-cancer drug therapies, we wanted to exploit homeostatic vulnerabilities within Tuberous Sclerosis Complex 2 (TSC2)-deficient cells with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivity. We show that nelfinavir and mefloquine synergize to selectively evoke a cytotoxic response in TSC2-deficient cell lines with mTORC1 hyperactivity. We optimize the concentrations of nelfinavir and mefloquine to a clinically viable range that kill cells that lack TSC2, while wild-type cells tolerate treatment. This new clinically viable drug combination causes a significant level of cell death in TSC2-deficient tumor spheroids. Furthermore, no cell recovery was apparent after drug withdrawal, revealing potent cytotoxicity. Transcriptional profiling by RNA sequencing of drug treated TSC2-deficient cells compared to wild-type cells suggested the cytotoxic mechanism of action, involving initial ER stress and an imbalance in energy homeostatic pathways. Further characterization revealed that supplementation with methyl pyruvate alleviated energy stress and reduced the cytotoxic effect, implicating energy deprivation as the trigger of cell death. This work underpins a critical vulnerability with cancer cells with aberrant signaling through the TSC2-mTORC1 pathway that lack flexibility in homeostatic pathways, which could be exploited with combined nelfinavir and mefloquine treatment.http://www.mdpi.com/2072-6694/10/10/375mTORnelfinavirmefloquineTSCcancer therapyenergy homeostasisER stress |
| spellingShingle | Henry D. McCann Charlotte E. Johnson Rachel J. Errington D. Mark Davies Elaine A. Dunlop Andrew R. Tee Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment Cancers mTOR nelfinavir mefloquine TSC cancer therapy energy homeostasis ER stress |
| title | Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment |
| title_full | Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment |
| title_fullStr | Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment |
| title_full_unstemmed | Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment |
| title_short | Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment |
| title_sort | energy stress mediated cytotoxicity in tuberous sclerosis complex 2 deficient cells with nelfinavir and mefloquine treatment |
| topic | mTOR nelfinavir mefloquine TSC cancer therapy energy homeostasis ER stress |
| url | http://www.mdpi.com/2072-6694/10/10/375 |
| work_keys_str_mv | AT henrydmccann energystressmediatedcytotoxicityintuberoussclerosiscomplex2deficientcellswithnelfinavirandmefloquinetreatment AT charlotteejohnson energystressmediatedcytotoxicityintuberoussclerosiscomplex2deficientcellswithnelfinavirandmefloquinetreatment AT racheljerrington energystressmediatedcytotoxicityintuberoussclerosiscomplex2deficientcellswithnelfinavirandmefloquinetreatment AT dmarkdavies energystressmediatedcytotoxicityintuberoussclerosiscomplex2deficientcellswithnelfinavirandmefloquinetreatment AT elaineadunlop energystressmediatedcytotoxicityintuberoussclerosiscomplex2deficientcellswithnelfinavirandmefloquinetreatment AT andrewrtee energystressmediatedcytotoxicityintuberoussclerosiscomplex2deficientcellswithnelfinavirandmefloquinetreatment |