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Research article
Complex Interactions of Lovastatin with 10 Chemotherapeutic Drugs: A Rigorous Evaluation of Synergism and Antagonism
Charles W. Putnam
University of Arizona Arizona Health Sciences Center
Corresponding Author
ORCiD: https://orcid.org/0000-0002-4487-9358
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Evidence bearing on the role of statins in the prevention and treatment of cancer is confounded by the diversity of statins, chemotherapeutic agents and cancer types included in the numerous published studies; consequently, the adjunctive value of statins with chemotherapy remains uncertain.
Methods
We assayed lovastatin in combination with each of ten commonly prescribed chemotherapy drugs in highly reproducible in vitro assays, using an indifferent cellular substrate, Saccharomyces cerevisiae. Cell density (OD600) data were analyzed for synergism and antagonism using the Loewe additivity model implemented with the Combenefit software.
Results
Four of the ten chemotherapy drugs – tamoxifen, doxorubicin, methotrexate and rapamycin – exhibited net synergism with lovastatin. The remaining six agents (5-fluorouracil, gemcitabine, epothilone, cisplatin, cyclophosphamide and etoposide) compiled neutral or antagonistic scores. Distinctive patterns of synergism and antagonism, often coexisting within the same concentration space, were documented with the various combinations, including those with net synergism scores.
Conclusions
The interactions of tamoxifen, doxorubicin, methotrexate and rapamycin with lovastatin suggest clinical utility and merit further exploration in cell lines and animal models. No less importantly, strong antagonistic interactions between certain agents and lovastatin argue for a cautious, data-driven approach before adding a statin to chemotherapeutic regimens. We also urge awareness of adventitious statin usage by patients entering cancer treatment protocols.
Keywords
Statins, chemotherapy, drug interaction, synergism, antagonism, Loewe model, Combenefit, dual drug assay, tamoxifen
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This preprint is under consideration at BMC Cancer. A preprint is 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
Complex Interactions of Lovastatin with 10 Chemotherapeutic Drugs: A Rigorous Evaluation of Synergism and Antagonism
Charles W. Putnam
University of Arizona Arizona Health Sciences Center
Corresponding Author
ORCiD: https://orcid.org/0000-0002-4487-9358
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: Under Revision
Version 1
Posted 02 Jun, 2020
No community comments so far
Editorial decision: Major revision
On 22 Nov, 2020
Review #4 received
Received 18 Nov, 2020
Reviewer #4 agreed
On 28 Oct, 2020
Review #2 received
Received 16 Oct, 2020
Review #3 received
Received 16 Oct, 2020
Reviewer #3 agreed
On 22 Sep, 2020
Reviewer #2 agreed
On 17 Sep, 2020
Review #1 received
Received 29 Jun, 2020
Reviewer #1 agreed
On 14 Jun, 2020
Reviewers invited
Invitations sent on 08 Jun, 2020
Editor assigned
On 21 May, 2020
First submitted
On 20 May, 2020
Submission checks complete
On 20 May, 2020
Editor invited
On 20 May, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Evidence bearing on the role of statins in the prevention and treatment of cancer is confounded by the diversity of statins, chemotherapeutic agents and cancer types included in the numerous published studies; consequently, the adjunctive value of statins with chemotherapy remains uncertain.
Methods
We assayed lovastatin in combination with each of ten commonly prescribed chemotherapy drugs in highly reproducible in vitro assays, using an indifferent cellular substrate, Saccharomyces cerevisiae. Cell density (OD600) data were analyzed for synergism and antagonism using the Loewe additivity model implemented with the Combenefit software.
Results
Four of the ten chemotherapy drugs – tamoxifen, doxorubicin, methotrexate and rapamycin – exhibited net synergism with lovastatin. The remaining six agents (5-fluorouracil, gemcitabine, epothilone, cisplatin, cyclophosphamide and etoposide) compiled neutral or antagonistic scores. Distinctive patterns of synergism and antagonism, often coexisting within the same concentration space, were documented with the various combinations, including those with net synergism scores.
Conclusions
The interactions of tamoxifen, doxorubicin, methotrexate and rapamycin with lovastatin suggest clinical utility and merit further exploration in cell lines and animal models. No less importantly, strong antagonistic interactions between certain agents and lovastatin argue for a cautious, data-driven approach before adding a statin to chemotherapeutic regimens. We also urge awareness of adventitious statin usage by patients entering cancer treatment protocols.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7