Statins inhibit proliferation and cytotoxicity of a human leukemic natural killer cell line

Abstract

BackgroundNatural killer cells comprise the body’s first line of defense against virus-infected cells. As is true of all lymphocytes, natural killer cell malignancies can develop, however natural killer cell leukemias can be very difficult to treat due to their intrinsic resistance to chemotherapeutic agents. With the recent understanding that statin drugs may have anti-cancer properties, our investigations have focused on the ability of statins to inhibit the growth and cytotoxicity of the YT-INDY natural killer cell leukemia cell line.ResultsOur findings indicate that several statin compounds can inhibit YT-INDY proliferation disrupt cell cycle progression and abrogate natural killer cell cytotoxicity. Since natural killer cell leukemia cytotoxicity may play a role in the pulmonary damage seen in these patients, this is an important finding. Cytotoxicity, proliferation and cell cycle progression could be restored by the addition of mevalonate, signifying that the statin effects are brought about through HMG CoA reductase inhibition. The mevalonate pathway intermediate geranylgeranyl pyrophosphate, but not other intermediates in the mevalonate pathway, partially reversed statin-induced inhibition of YT-INDY proliferation and cytotoxicity. These results suggest that blockage of products made in the latter part of the mevalonate pathway may account for the observed inhibitory effects on YT-INDY proliferation and cytotoxicity. However, geranylgeranyl pyrophosphate could not reverse the statin-induced inhibition of the cell cycle.ConclusionsThese results suggest that the statin drugs should be investigated as a potential therapeutic strategy for human natural killer cell leukemias possibly in combination with chemotherapeutic agents.

The Effect of Statins on Blood Gene Expression in COPD

“…The second correlated expression profile with statin use was a signature of improved prognosis among pediatric acute myeloid leukemia patients (AML). In tumor cell lines, statins were shown to inhibit the growth of acute myeloid leukemia cells [ 51 ], to synergistically increase the killing of the human erythroleukemia cell line K562 by the chemotherapeutic agent cytosine arabinoside [ 52 ], and to inhibit the proliferation and cytotoxicity of a human leukemic natural killer cell line [ 53 ]. The third correlated signature with statin use was a signature of Parkinson’s disease (PD) patients when compared with healthy or neurodegenerative disease controls[ 54 ].…”

Predicting the effect of statins on cancer risk using genetic variants: a Mendelian randomization study in UK Biobank

“…Statins are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), which is the rate-limiting enzyme in the melavonate pathway; a pathway producing a range of cell signalling molecules with the potential to regulate oncogenesis. This is supported by strong laboratory evidence that statins induce anticarcinogenic effects on cell proliferation and survival in various cell lines [1][2][3][4] , and reduce tumour growth in a range of in vivo models [5][6][7][8][9][10] .…”

Atorvastatin-Induced Inhibition of Human Melanoma In Vivo Development

“…These data strongly suggest that in our experimental nude mouse model, the atorvastatin-induced control of subcutaneous melanoma growth is dependent on NK cell activity. Moreover, previous studies of the anti-inflammatory effects of atorvastatin [23,24] suggest that in our experiments the atorvastatininduced increase in activated (CD69 + ) NK cells is not linked to a direct effect of atorvastatin on NK cells but is more likely due to atorvastatininduced MICA overexpression in melanoma cells. However, intraperitoneal statin injections induce systemic disruptions, which could also interfere with the innate anti-melanoma immune response by acting on Tγδ cells.…”

“…Our previous papers have shown that inhibition of RhoA/ROCK activity favors anti-melanoma immune response through MHC-class I, costimulatory molecules and FasL overexpression on melanoma cells membrane [3][4][5]. Furthermore, as previously described, the inhibition of ROCK activity reduces melanoma cells migration, invasion and metastases [23][24][25][26][27]. Consequently Atorvastatin pre-treatment of WM-266-4 cells at 1 μM mainly reduces local tumor growth and metastasis development through MICA overexpression and NK cell activity.…”