minocycline and Carcinoma--Hepatocellular

Targeting mitochondrial metabolism has been recently demonstrated to be a promising therapeutic strategy for the treatment of various cancer. In this work, we demonstrate that antibiotic tigecycline is selectively against hepatocellular carcinoma (HCC) through inducing mitochondrial dysfunction and oxidative damage. Tigecycline is more effective in inhibiting proliferation and inducing apoptosis of HCC than normal liver cells. Importantly, tigecycline significantly enhances the inhibitory effects of chemotherapeutic drug cisplatin in HCC in vitro and in vivo. Mechanistically, tigecycline specifically inhibits mitochondrial translation as shown by the decreased protein levels of Cox-1 and -2 but not Cox-4 or Grp78, and increased mRNA levels of Cox-1 and -2 but not Cox-4 in HCC cells exposed to tigecycline. In addition, tigecycline significantly induces mitochondrial dysfunction in HCC cells via decreasing mitochondrial membrane potential, complex I and IV activities, mitochondrial respiration and ATP levels. Tigecycline also increases levels of mitochondrial superoxide, hydrogen peroxide and ROS levels. Consistent with oxidative stress, oxidative damage on DNA, protein and lipid are also observed in tigecycline-treated cells. Importantly, antioxidant N-acetyl-l-cysteine (NAC) reverses the effects of tigecycline, suggesting that oxidative stress is required for the action of tigecycline in HCC cells. We further show that HCC cells have higher level of mitochondrial biogenesis than normal liver cells which might explain the different sensitivity to tigecycline between HCC and normal liver cells. Our work is the first to demonstrate that tigecycline is a promising candidate for HCC treatment and highlight the therapeutic value of targeting mitochondrial metabolism in HCC.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Synergism; Endoplasmic Reticulum Chaperone BiP; Hep G2 Cells; Humans; Liver Neoplasms; Membrane Potential, Mitochondrial; Mice; Mice, SCID; Minocycline; Mitochondria, Liver; Oxidative Stress; Tigecycline; Xenograft Model Antitumor Assays

Minocycline, a semisynthetic tetracycline, is a highly lipophilic molecule capable of infiltrating tissues and blood. Previous studies have revealed the functions and mechanisms of minocycline in anti-inflammation, protection of the nervous system and certain tumors. The role of minocycline has never been investigated in hepatocellular carcinoma (HCC). The functions of minocycline on HCC cells were investigated using immunohistochemical staining and western blotting. Minocycline was applied to L02, HepG2 and Huh7 cells, and the growth characteristics were studied. Cisplatin was administered in combination with minocycline in this study. Cell cycle and apoptosis analyses were employed to investigate the mechanisms underlying the growth regulation associated with minocycline and(or) cisplatin. Minocycline caused S phase cell cycle arrest and an increase in the apoptotic rate associated with upregulation of p27, cleaved-caspase8, cleaved-caspase3 and cleaved-PRAP-1. Low dose of cisplatin promoted cell cycle arrest and apoptosis, whereas minocycline was mainly associated with upregulation of cleaved-PARP-1. The combination of cisplatin and minocycline increased the rate and extent of cell cycle arrest and increased the apoptosis rate caused by minocycline. A novel mechanism was revealed. Minocycline functions as an antitumor drug in HCC by regulating p27, caspase-3 and PARP-1. Cisplatin enhanced minocycline's effect on PARP-1.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Cell Cycle Checkpoints; Cell Line, Tumor; Cisplatin; Drug Synergism; Hep G2 Cells; Humans; Liver Neoplasms; Mice; Mice, Inbred BALB C; Minocycline; Xenograft Model Antitumor Assays

Topics: Adult; Anti-Bacterial Agents; Brucella melitensis; Brucellosis; Carcinoma, Hepatocellular; Graft Rejection; Hepatitis C; Humans; Liver Failure; Liver Neoplasms; Liver Transplantation; Male; Minocycline; Reoperation; Tigecycline; Treatment Outcome

Topics: Aged; Bile; Carcinoma, Hepatocellular; Cholelithiasis; Humans; Infusions, Parenteral; Liver Neoplasms; Male; Middle Aged; Minocycline; Postoperative Complications; Tetracycline; Time Factors