Suppression of multiple myeloma by mitochondrial targeting
Abstract Treatment of multiple myeloma (MM) aims at inducing cell apoptosis by surpassing the limited capacity of MM cells to cope with oxidative stress. MM cell survival may further be suppressed by limiting cellular cholesterol. Long-chain fatty acid analogs of the MEDICA series promote mitochondr...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2021-03-01
|
| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-021-83829-2 |
| _version_ | 1818425547735171072 |
|---|---|
| author | Yana Aisen Moshe E. Gatt Rachel Hertz Elia Smeir Jacob Bar-Tana |
| author_facet | Yana Aisen Moshe E. Gatt Rachel Hertz Elia Smeir Jacob Bar-Tana |
| author_sort | Yana Aisen |
| collection | DOAJ |
| description | Abstract Treatment of multiple myeloma (MM) aims at inducing cell apoptosis by surpassing the limited capacity of MM cells to cope with oxidative stress. MM cell survival may further be suppressed by limiting cellular cholesterol. Long-chain fatty acid analogs of the MEDICA series promote mitochondrial stress and inhibit cholesterol biosynthesis, thus prompting us to verify their efficacy and mode-of-action in suppressing MM cell survival, in comparison to bortezomib. MEDICA analog is shown here to effectively suppress survival of MM cells, and to inhibit growth of MM xenograft. Suppression of MM cell survival by MEDICA is accompanied by inhibition of the STAT3, MAPK and the mTORC1 transduction pathways due to mitochondrial oxidative stress. MEDICA-induced oxidative stress is abrogated by added exogenous cholesterol. Suppression of MM cell survival by bortezomib is similarly driven by bortezomib-induced oxidative stress, being abrogated by added cholesterol. In line with that, the time-to-best-response of MM patients to bortezomib-based treatment protocols is shown to be positively correlated with their plasma cholesterol level. MEDICA profile may indicate novel therapeutic potential in the management of MM. |
| first_indexed | 2024-12-14T14:15:41Z |
| format | Article |
| id | doaj.art-48da890086fd45d8856e963201073334 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T14:15:41Z |
| publishDate | 2021-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-48da890086fd45d8856e9632010733342022-12-21T22:58:11ZengNature PortfolioScientific Reports2045-23222021-03-0111111010.1038/s41598-021-83829-2Suppression of multiple myeloma by mitochondrial targetingYana Aisen0Moshe E. Gatt1Rachel Hertz2Elia Smeir3Jacob Bar-Tana4Department of Human Nutrition and Metabolism, Hebrew University Medical SchoolDepartment of Hematology, Hadassah Medical CenterDepartment of Human Nutrition and Metabolism, Hebrew University Medical SchoolDepartment of Human Nutrition and Metabolism, Hebrew University Medical SchoolDepartment of Human Nutrition and Metabolism, Hebrew University Medical SchoolAbstract Treatment of multiple myeloma (MM) aims at inducing cell apoptosis by surpassing the limited capacity of MM cells to cope with oxidative stress. MM cell survival may further be suppressed by limiting cellular cholesterol. Long-chain fatty acid analogs of the MEDICA series promote mitochondrial stress and inhibit cholesterol biosynthesis, thus prompting us to verify their efficacy and mode-of-action in suppressing MM cell survival, in comparison to bortezomib. MEDICA analog is shown here to effectively suppress survival of MM cells, and to inhibit growth of MM xenograft. Suppression of MM cell survival by MEDICA is accompanied by inhibition of the STAT3, MAPK and the mTORC1 transduction pathways due to mitochondrial oxidative stress. MEDICA-induced oxidative stress is abrogated by added exogenous cholesterol. Suppression of MM cell survival by bortezomib is similarly driven by bortezomib-induced oxidative stress, being abrogated by added cholesterol. In line with that, the time-to-best-response of MM patients to bortezomib-based treatment protocols is shown to be positively correlated with their plasma cholesterol level. MEDICA profile may indicate novel therapeutic potential in the management of MM.https://doi.org/10.1038/s41598-021-83829-2 |
| spellingShingle | Yana Aisen Moshe E. Gatt Rachel Hertz Elia Smeir Jacob Bar-Tana Suppression of multiple myeloma by mitochondrial targeting Scientific Reports |
| title | Suppression of multiple myeloma by mitochondrial targeting |
| title_full | Suppression of multiple myeloma by mitochondrial targeting |
| title_fullStr | Suppression of multiple myeloma by mitochondrial targeting |
| title_full_unstemmed | Suppression of multiple myeloma by mitochondrial targeting |
| title_short | Suppression of multiple myeloma by mitochondrial targeting |
| title_sort | suppression of multiple myeloma by mitochondrial targeting |
| url | https://doi.org/10.1038/s41598-021-83829-2 |
| work_keys_str_mv | AT yanaaisen suppressionofmultiplemyelomabymitochondrialtargeting AT mosheegatt suppressionofmultiplemyelomabymitochondrialtargeting AT rachelhertz suppressionofmultiplemyelomabymitochondrialtargeting AT eliasmeir suppressionofmultiplemyelomabymitochondrialtargeting AT jacobbartana suppressionofmultiplemyelomabymitochondrialtargeting |