Complex Interactions of Lovastatin with 10 Chemotherapeutic Drugs: A Rigorous Evaluation of Synergism and Antagonism
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.
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.
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.
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.
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Posted 02 Jun, 2020
On 22 Nov, 2020
Received 18 Nov, 2020
On 28 Oct, 2020
Received 16 Oct, 2020
Received 16 Oct, 2020
On 22 Sep, 2020
On 17 Sep, 2020
Received 29 Jun, 2020
On 14 Jun, 2020
Invitations sent on 08 Jun, 2020
On 21 May, 2020
On 20 May, 2020
On 20 May, 2020
On 20 May, 2020
Complex Interactions of Lovastatin with 10 Chemotherapeutic Drugs: A Rigorous Evaluation of Synergism and Antagonism
Posted 02 Jun, 2020
On 22 Nov, 2020
Received 18 Nov, 2020
On 28 Oct, 2020
Received 16 Oct, 2020
Received 16 Oct, 2020
On 22 Sep, 2020
On 17 Sep, 2020
Received 29 Jun, 2020
On 14 Jun, 2020
Invitations sent on 08 Jun, 2020
On 21 May, 2020
On 20 May, 2020
On 20 May, 2020
On 20 May, 2020
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.
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.
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.
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