Synergistic antitumor effects of atorvastatin and chemotherapies: In vitro and in vivo studies

Atorvastatin (ATOR) acts on certain antitumor pathways; the consequences of chemotherapies continue to be a major concern, notwithstanding the increased efficacy provided by contemporary therapies. This study investigated the synergistic effects and underlying mechanisms of different treatment protocols using ATOR on the THP-1 cell line and on lung cancer in mice. For the in vitro study, an MTT assay was performed, and then different combinations against the THP-1 cell line were used as follows: non-treated cells, THP-1/ATOR IC50, THP-1/ cytarabine (CYT) IC50, THP-1/doxorubicin (DOX) IC50, THP-1/DOX/CYT, THP-1/ATOR/CYT, THP-1/ATOR/ DOX, and THP-1/ATOR/CYT/DOX. For the in vivo study, CD-1 male mice were used; G1 was the normal control. Gs2-5 were administered with urethane (Ure) and butylated hydroxytoluene (BHT). G2 was the positive control. G3 was treated with ATOR (20 mg/kg). G4 was treated with Bevacizumab (Bev) (5 mg/kg). G5 was cotreated with ATOR/Bev. Histopathological and immunohistochemical investigations, flow cytometry and molecular analysis of PI3K, Akt, and mTOR genes were performed after different treatment protocols. The results showed that different combinatorial treatment settings of ATOR in vitro increase the apoptotic-inducing capacity and cell cycle arrest. Co-treatment with ATOR and Bev led to a significant decrease in S-phase and G2/M percentages. Furthermore, in vivo co-treatment with ATOR/Bev decreased tumor incidence and size with a significant reduction of the immunohistochemical PCNA (LI%) in lung parenchyma, targeting PI3K/Akt/mTOR, and VEGF-A signaling pathways. Co-treatment with ATOR and chemotherapies led to cell cycle arrest, modulation of the PI3K/Akt/mTOR, and VEGF-A signaling pathways in tumor cells.