TY - JOUR
T1 - Screening a library of approved drugs reveals that prednisolone synergizes with pitavastatin to induce ovarian cancer cell death
AU - Abdullah, Marwan Ibrahim
AU - Abed, Mohammed Najim
AU - Khanim, Farhat
AU - Richardson, Alan
PY - 2019/12/1
Y1 - 2019/12/1
N2 - The survival rate for patients with ovarian cancer has changed little in the past three decades since the introduction of platinum-based chemotherapy and new drugs are needed. Statins are drugs used for the treatment and prevention of cardiovascular diseases. Recent work from our laboratory has shown that pitavastatin has potential as a treatment for ovarian cancer if dietary geranylgeraniol is controlled. However, relatively high doses of statins are required to induce apoptosis in cancer cells, increasing the risk of myopathy, the most common adverse effect associated with statins. This makes it desirable to identify drugs which reduce the dose of pitavastatin necessary to treat cancer. A drug-repositioning strategy was employed to identify suitable candidates. Screening a custom library of 100 off-patent drugs for synergistic activity with pitavastatin identified prednisolone as the most prominent hit. Prednisolone potentiated the activity of pitavastatin in several assays measuring the growth, survival or apoptosis in several ovarian cancer cells lines. Prednisolone, alone or in some cases in combination with pitavastatin, reduced the expression of genes encoding enzymes in the mevalonate pathway, providing a mechanistic explanation for the synergy.
AB - The survival rate for patients with ovarian cancer has changed little in the past three decades since the introduction of platinum-based chemotherapy and new drugs are needed. Statins are drugs used for the treatment and prevention of cardiovascular diseases. Recent work from our laboratory has shown that pitavastatin has potential as a treatment for ovarian cancer if dietary geranylgeraniol is controlled. However, relatively high doses of statins are required to induce apoptosis in cancer cells, increasing the risk of myopathy, the most common adverse effect associated with statins. This makes it desirable to identify drugs which reduce the dose of pitavastatin necessary to treat cancer. A drug-repositioning strategy was employed to identify suitable candidates. Screening a custom library of 100 off-patent drugs for synergistic activity with pitavastatin identified prednisolone as the most prominent hit. Prednisolone potentiated the activity of pitavastatin in several assays measuring the growth, survival or apoptosis in several ovarian cancer cells lines. Prednisolone, alone or in some cases in combination with pitavastatin, reduced the expression of genes encoding enzymes in the mevalonate pathway, providing a mechanistic explanation for the synergy.
UR - http://www.scopus.com/inward/record.url?scp=85069267243&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-46102-1
DO - 10.1038/s41598-019-46102-1
M3 - Article
C2 - 31270377
AN - SCOPUS:85069267243
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 9632
ER -