title: In vitro and in vivo anticancer effects of mevalonate pathway modulation on human cancer cells.
abstract: BACKGROUND
  The increasing usage of statins (the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) has revealed a number of unexpected beneficial effects, including a reduction in cancer risk.
  
  
  METHODS
  We investigated the direct anticancer effects of different statins approved for clinical use on human breast and brain cancer cells. We also explored the effects of statins on cancer cells using in silico simulations.
  
  
  RESULTS
  In vitro studies showed that cerivastatin, pitavastatin, and fluvastatin were the most potent anti-proliferative, autophagy inducing agents in human cancer cells including stem cell-like primary glioblastoma cell lines. Consistently, pitavastatin was more effective than fluvastatin in inhibiting U87 tumour growth in vivo. Intraperitoneal injection was much better than oral administration in delaying glioblastoma growth. Following statin treatment, tumour cells were rescued by adding mevalonate and geranylgeranyl pyrophosphate. Knockdown of geranylgeranyl pyrophosphate synthetase-1 also induced strong cell autophagy and cell death in vitro and reduced U87 tumour growth in vivo. These data demonstrate that statins main effect is via targeting the mevalonate synthesis pathway in tumour cells.
  
  
  CONCLUSIONS
  Our study demonstrates the potent anticancer effects of statins. These safe and well-tolerated drugs need to be further investigated as cancer chemotherapeutics in comprehensive clinical studies.
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: P
authors.initials: P
authors.lastname: Jiang
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: R
authors.initials: R
authors.lastname: Mukthavaram
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Chao
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: N
authors.initials: N
authors.lastname: Nomura
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: I S
authors.initials: IS
authors.lastname: Bharati
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: V
authors.initials: V
authors.lastname: Fogal
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: S
authors.initials: S
authors.lastname: Pastorino
authors.affiliation: Departments of Bioengineering and Medicine and Institute of Engineering in Medicine, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: D
authors.initials: D
authors.lastname: Teng
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: X
authors.initials: X
authors.lastname: Cong
authors.affiliation: Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Pingle
authors.affiliation: Cellworks Group, Inc., 2025 Gateway Place, Suite 265, San Jose, CA 95110, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kapoor
authors.affiliation: Cellworks Group, Inc., 2025 Gateway Place, Suite 265, San Jose, CA 95110, USA.
authors.forename: K
authors.initials: K
authors.lastname: Shetty
authors.affiliation: Cellworks Group, Inc., 2025 Gateway Place, Suite 265, San Jose, CA 95110, USA.
authors.forename: A
authors.initials: A
authors.lastname: Aggrawal
authors.affiliation: Cellworks Group, Inc., 2025 Gateway Place, Suite 265, San Jose, CA 95110, USA.
authors.forename: S
authors.initials: S
authors.lastname: Vali
authors.affiliation: Cellworks Group, Inc., 2025 Gateway Place, Suite 265, San Jose, CA 95110, USA.
authors.forename: T
authors.initials: T
authors.lastname: Abbasi
authors.affiliation: Departments of Bioengineering and Medicine and Institute of Engineering in Medicine, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chien
authors.affiliation: 1] Translational Neuro-Oncology Laboratories, Moores Cancer Center, UC San Diego, La Jolla, CA 92093, USA [2] Department of Neurosciences, UC San Diego, La Jolla, CA 92093, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kesari
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004195:Disease Models, Animal; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D066298:In Vitro Techniques; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude
chemical_list: D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008798:Mevalonic Acid
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