First clinical experience with simvastatin to overcome drug resistance in refractory multiple myeloma

Abstract

In vitro statins overcome cell adhesion-mediated drug resistance at non-toxic concentrations that are achievable in humans by standard dose simvastatin. A pilot phase-II trial was initiated to determine feasibility and antimyeloma efficacy. In six myeloma patients refractory to two cycles of bortezomib or bendamustine simvastatin was concomitantly administered during further two cycles. The therapy was well tolerated without grade 3/4 toxicity. Intrapatient (cycles I/II vs. III/IV) and interpatient comparison (vs. ten patients without simvastatin) showed reduction of drug resistance by inhibition of HMG-CoA-reductase. In summary, this is the first phase II experience to study antimyeloma activity of statins in humans.

The Hedgehog Receptor Patched Functions in Multidrug Transport and Chemotherapy Resistance

“…Several studies have reported that statins inhibits proliferation and cell division of cancer cells (44,45), and clinical trials have shown that the addition of statins to traditional chemotherapeutic strategies can increase the efficacy of chemotherapy (46,47). In particular, Martirosyan and colleagues (36) recently showed that lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin, which is used in the treatment of primary and relapsed drug-resistant ovarian cancer.…”

Proteasome Inhibitors in Cancer Therapy: Lessons from the First Decade

“…The former may have some applicability to bortezomib as P-glycoprotein blockade enhanced bortezomib sensitivity in models of leukemia (113) and Ewing's sarcoma (114). Another approach to overcome acquired resistance may be to block 3-hydroxy-3-methyl-glutaryl-CoA reductase (115), although the mechanism involved has not been defined. Further studies will be needed with in vitro preclinical models of bortezomib resistance, ideally validated with clinical samples from patients with acquired resistance, to better delineate the relevant mechanisms in vivo and test targeted approaches to abrogate these pathways.…”

Statins are potential anticancerous agents (Review)

“…Statins exert antiproliferative, pro-apoptotic and anti-invasive effects in different cancer cell lines with varying sensitivity. The antimyeloma activity of statins in humans was first reported with the concomitant simvastatin administration in refractory multiple myeloma (MM), which showed reduced drug resistance (18). However, high-dose simvastatin treatment (15 mg/kg/day) in heavily pretreated MM patients transiently increased osteoclast activity and gastrointestinal side-effects, leading to premature discontinuation (19).…”