Effect of mitochondrially targeted carboxy proxyl nitroxide on Akt-mediated survival in Daudi cells: Significance of a dual mode of action.
Vicious cycles of mutations and reactive oxygen species (ROS) generation contribute to cancer progression. The use of antioxidants to inhibit ROS generation promotes cytostasis by affecting the mutation cycle and ROS-dependent survival signaling. However, cancer cells select mutations to elevate ROS...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5398517?pdf=render |
| _version_ | 1828840157015441408 |
|---|---|
| author | Gokul Variar Tarun Pant Apoorva Singh Abinaya Ravichandran Sushant Swami Balaraman Kalyanaraman Anuradha Dhanasekaran |
| author_facet | Gokul Variar Tarun Pant Apoorva Singh Abinaya Ravichandran Sushant Swami Balaraman Kalyanaraman Anuradha Dhanasekaran |
| author_sort | Gokul Variar |
| collection | DOAJ |
| description | Vicious cycles of mutations and reactive oxygen species (ROS) generation contribute to cancer progression. The use of antioxidants to inhibit ROS generation promotes cytostasis by affecting the mutation cycle and ROS-dependent survival signaling. However, cancer cells select mutations to elevate ROS albeit maintaining mitochondrial hyperpolarization (Δψm), even under hypoxia. From this perspective, the use of drugs that disrupt both ROS generation and Δψm is a viable anticancer strategy. Hence, we studied the effects of mitochondrially targeted carboxy proxyl nitroxide (Mito-CP) and a control ten carbon TPP moiety (Dec-TPP+) in the human Burkitt lymphoma cell line (Daudi) and normal peripheral blood mononuclear cells under hypoxia and normoxia. We found preferential localization, Δψm and adenosine triphosphate loss, and significant cytotoxicity by Mito-CP in Daudi cells alone. Interestingly, ROS levels were decreased and maintained in hypoxic and normoxic cancer cells, respectively, by Mito-CP but not Dec-TPP+, therefore preventing any adaptive signaling. Moreover, dual effects on mitochondrial bioenergetics and ROS by Mito-CP curtailed the cancer survival via Akt inhibition, AMPK-HIF-1α activation and promoted apoptosis via increased BCL2-associated X protein and poly (ADP-ribose) polymerase expression. This dual mode of action by Mito-CP provides a better explanation of the application of antioxidants with specific relevance to cancerous transformation and adaptations in the Daudi cell line. |
| first_indexed | 2024-12-12T19:35:59Z |
| format | Article |
| id | doaj.art-15c922123b7c498293ba0ac1dedb6f4a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T19:35:59Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-15c922123b7c498293ba0ac1dedb6f4a2022-12-22T00:14:18ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01124e017454610.1371/journal.pone.0174546Effect of mitochondrially targeted carboxy proxyl nitroxide on Akt-mediated survival in Daudi cells: Significance of a dual mode of action.Gokul VariarTarun PantApoorva SinghAbinaya RavichandranSushant SwamiBalaraman KalyanaramanAnuradha DhanasekaranVicious cycles of mutations and reactive oxygen species (ROS) generation contribute to cancer progression. The use of antioxidants to inhibit ROS generation promotes cytostasis by affecting the mutation cycle and ROS-dependent survival signaling. However, cancer cells select mutations to elevate ROS albeit maintaining mitochondrial hyperpolarization (Δψm), even under hypoxia. From this perspective, the use of drugs that disrupt both ROS generation and Δψm is a viable anticancer strategy. Hence, we studied the effects of mitochondrially targeted carboxy proxyl nitroxide (Mito-CP) and a control ten carbon TPP moiety (Dec-TPP+) in the human Burkitt lymphoma cell line (Daudi) and normal peripheral blood mononuclear cells under hypoxia and normoxia. We found preferential localization, Δψm and adenosine triphosphate loss, and significant cytotoxicity by Mito-CP in Daudi cells alone. Interestingly, ROS levels were decreased and maintained in hypoxic and normoxic cancer cells, respectively, by Mito-CP but not Dec-TPP+, therefore preventing any adaptive signaling. Moreover, dual effects on mitochondrial bioenergetics and ROS by Mito-CP curtailed the cancer survival via Akt inhibition, AMPK-HIF-1α activation and promoted apoptosis via increased BCL2-associated X protein and poly (ADP-ribose) polymerase expression. This dual mode of action by Mito-CP provides a better explanation of the application of antioxidants with specific relevance to cancerous transformation and adaptations in the Daudi cell line.http://europepmc.org/articles/PMC5398517?pdf=render |
| spellingShingle | Gokul Variar Tarun Pant Apoorva Singh Abinaya Ravichandran Sushant Swami Balaraman Kalyanaraman Anuradha Dhanasekaran Effect of mitochondrially targeted carboxy proxyl nitroxide on Akt-mediated survival in Daudi cells: Significance of a dual mode of action. PLoS ONE |
| title | Effect of mitochondrially targeted carboxy proxyl nitroxide on Akt-mediated survival in Daudi cells: Significance of a dual mode of action. |
| title_full | Effect of mitochondrially targeted carboxy proxyl nitroxide on Akt-mediated survival in Daudi cells: Significance of a dual mode of action. |
| title_fullStr | Effect of mitochondrially targeted carboxy proxyl nitroxide on Akt-mediated survival in Daudi cells: Significance of a dual mode of action. |
| title_full_unstemmed | Effect of mitochondrially targeted carboxy proxyl nitroxide on Akt-mediated survival in Daudi cells: Significance of a dual mode of action. |
| title_short | Effect of mitochondrially targeted carboxy proxyl nitroxide on Akt-mediated survival in Daudi cells: Significance of a dual mode of action. |
| title_sort | effect of mitochondrially targeted carboxy proxyl nitroxide on akt mediated survival in daudi cells significance of a dual mode of action |
| url | http://europepmc.org/articles/PMC5398517?pdf=render |
| work_keys_str_mv | AT gokulvariar effectofmitochondriallytargetedcarboxyproxylnitroxideonaktmediatedsurvivalindaudicellssignificanceofadualmodeofaction AT tarunpant effectofmitochondriallytargetedcarboxyproxylnitroxideonaktmediatedsurvivalindaudicellssignificanceofadualmodeofaction AT apoorvasingh effectofmitochondriallytargetedcarboxyproxylnitroxideonaktmediatedsurvivalindaudicellssignificanceofadualmodeofaction AT abinayaravichandran effectofmitochondriallytargetedcarboxyproxylnitroxideonaktmediatedsurvivalindaudicellssignificanceofadualmodeofaction AT sushantswami effectofmitochondriallytargetedcarboxyproxylnitroxideonaktmediatedsurvivalindaudicellssignificanceofadualmodeofaction AT balaramankalyanaraman effectofmitochondriallytargetedcarboxyproxylnitroxideonaktmediatedsurvivalindaudicellssignificanceofadualmodeofaction AT anuradhadhanasekaran effectofmitochondriallytargetedcarboxyproxylnitroxideonaktmediatedsurvivalindaudicellssignificanceofadualmodeofaction |