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Background
Mitochondria are considered a primary intracellular site of reactive oxygen species (ROS) generation. Generally, cancer cells with mitochondrial genetic abnormalities (copy number change and mutations) have escalated ROS levels compared to normal cells. Since high levels of ROS can trigger apoptosis, treating cancer cells with low doses of mitochondria-targeting / ROS-stimulating agents may offer cancer-specific therapy. This study aimed to investigate how baseline ROS levels might influence cancer cells’ response to ROS-stimulating therapy.
Methods
Four cancer and one normal cell lines were treated with a conventional drug (cisplatin) and a mitochondria-targeting agent (dequalinium chloride hydrate) separately and jointly. Cell viability was assessed and drug combination synergisms were indicated by the combination index (CI). Mitochondrial DNA copy number (mtDNAcn), ROS and mitochondrial membrane potential (MMP) were measured, and the relative expression levels of the genes and proteins involved in ROS-mediated apoptosis pathways were also investigated.
Results
Our data showed a correlation between the baseline ROS level, mtDNAcn and drug sensitivity in the tested cells. Synergistic effect of both drugs was also observed with ROS being the key contributor in cell death.
Conclusions
Our findings suggest that mitochondria-targeting therapy could be more effective compared to conventional treatments. In addition, cancer cells with low levels of ROS may be more sensitive to the treatment, while cells with high levels of ROS may be more resistant. Doubtlessly, further studies employing a wider range of cell lines and in vivo experiments are needed to validate our results. However, this study provides an insight into understanding the influence of intracellular ROS on drug sensitivity, and may lead to the development of new therapeutic strategies to improve efficacy of anticancer therapy.
Keywords
Reactive oxygen species, cisplatin, dequalinium chloride hydrate, drug sensitivity, cancer biomarker
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CURRENT STATUS: Published
View the published article at BMC Cancer.
Version 4
Posted 19 Dec, 2019
No community comments so far
Editorial decision: Accept
On 05 Dec, 2019
Editor assigned
On 04 Dec, 2019
Submission checks complete
On 03 Dec, 2019
Editor invited
On 03 Dec, 2019
No comments provided
Editorial decision: Minor revision
On 02 Dec, 2019
Editor assigned
On 20 Nov, 2019
Submission checks complete
On 19 Nov, 2019
Editor invited
On 19 Nov, 2019
No comments provided
Editorial decision: Minor revision
On 31 Oct, 2019
Review #3 received
Received 30 Oct, 2019
Review #2 received
Received 22 Oct, 2019
Reviewer #2 agreed
On 09 Oct, 2019
Reviewer #3 agreed
On 09 Oct, 2019
Review #1 received
Received 07 Oct, 2019
Reviewers invited
Invitations sent on 01 Oct, 2019
Reviewer #1 agreed
On 01 Oct, 2019
Editor assigned
On 16 Sep, 2019
Submission checks complete
On 15 Sep, 2019
Editor invited
On 15 Sep, 2019
No comments provided
Editorial decision: Major revision
On 22 Aug, 2019
Review #1 received
Received 16 Aug, 2019
Review #2 received
Received 06 Aug, 2019
Reviewer #2 agreed
On 03 Aug, 2019
Reviewers invited
Invitations sent on 31 Jul, 2019
Reviewer #1 agreed
On 31 Jul, 2019
Submission checks complete
On 19 Jul, 2019
Editor assigned
On 08 Jul, 2019
Editor invited
On 07 Jul, 2019
First submitted
On 04 Jul, 2019
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See the published version of this preprint at BMC Cancer.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at BMC Cancer.
Version 4
Posted 19 Dec, 2019
No community comments so far
Editorial decision: Accept
On 05 Dec, 2019
Editor assigned
On 04 Dec, 2019
Submission checks complete
On 03 Dec, 2019
Editor invited
On 03 Dec, 2019
No comments provided
Editorial decision: Minor revision
On 02 Dec, 2019
Editor assigned
On 20 Nov, 2019
Submission checks complete
On 19 Nov, 2019
Editor invited
On 19 Nov, 2019
No comments provided
Editorial decision: Minor revision
On 31 Oct, 2019
Review #3 received
Received 30 Oct, 2019
Review #2 received
Received 22 Oct, 2019
Reviewer #2 agreed
On 09 Oct, 2019
Reviewer #3 agreed
On 09 Oct, 2019
Review #1 received
Received 07 Oct, 2019
Reviewers invited
Invitations sent on 01 Oct, 2019
Reviewer #1 agreed
On 01 Oct, 2019
Editor assigned
On 16 Sep, 2019
Submission checks complete
On 15 Sep, 2019
Editor invited
On 15 Sep, 2019
No comments provided
Editorial decision: Major revision
On 22 Aug, 2019
Review #1 received
Received 16 Aug, 2019
Review #2 received
Received 06 Aug, 2019
Reviewer #2 agreed
On 03 Aug, 2019
Reviewers invited
Invitations sent on 31 Jul, 2019
Reviewer #1 agreed
On 31 Jul, 2019
Submission checks complete
On 19 Jul, 2019
Editor assigned
On 08 Jul, 2019
Editor invited
On 07 Jul, 2019
First submitted
On 04 Jul, 2019
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at BMC Cancer.
Background
Mitochondria are considered a primary intracellular site of reactive oxygen species (ROS) generation. Generally, cancer cells with mitochondrial genetic abnormalities (copy number change and mutations) have escalated ROS levels compared to normal cells. Since high levels of ROS can trigger apoptosis, treating cancer cells with low doses of mitochondria-targeting / ROS-stimulating agents may offer cancer-specific therapy. This study aimed to investigate how baseline ROS levels might influence cancer cells’ response to ROS-stimulating therapy.
Methods
Four cancer and one normal cell lines were treated with a conventional drug (cisplatin) and a mitochondria-targeting agent (dequalinium chloride hydrate) separately and jointly. Cell viability was assessed and drug combination synergisms were indicated by the combination index (CI). Mitochondrial DNA copy number (mtDNAcn), ROS and mitochondrial membrane potential (MMP) were measured, and the relative expression levels of the genes and proteins involved in ROS-mediated apoptosis pathways were also investigated.
Results
Our data showed a correlation between the baseline ROS level, mtDNAcn and drug sensitivity in the tested cells. Synergistic effect of both drugs was also observed with ROS being the key contributor in cell death.
Conclusions
Our findings suggest that mitochondria-targeting therapy could be more effective compared to conventional treatments. In addition, cancer cells with low levels of ROS may be more sensitive to the treatment, while cells with high levels of ROS may be more resistant. Doubtlessly, further studies employing a wider range of cell lines and in vivo experiments are needed to validate our results. However, this study provides an insight into understanding the influence of intracellular ROS on drug sensitivity, and may lead to the development of new therapeutic strategies to improve efficacy of anticancer therapy.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
This is a list of supplementary files associated with this preprint. Click to download.
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