minocycline and Liver-Neoplasms

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

Although the anti-EGFR monoclonal antibody panitumumab is effective in treating colorectal cancer, the occurrence of severe skin disorders often discontinues therapy. Herein, we investigated by a retrospective chart review the effect of prophylactic oral minocycline in combination with skin treatment using moisturizer on the incidence of skin disorders and tumor response in metastatic colorectal cancer patients who received panitumumab.. In a total of 55 patients, 38 patients were eligible, consisting the pre-emptive group (N=25) and reactive group (N=13). Acneiform rash and other adverse events were graded according to the CTCAE v4.0.. The occurrence of acneiform rash (grade ≥2) was significantly lower in pre-emptive group than in reactive group (44.0% vs. 84.6%, p=0.04). No significant differences in the occurrence of other adverse events were observed between the two groups. Tumor response was not significantly different between the two groups (36.0% vs. 7.7%, OR, 6.75; 95% confidence interval (CI)=0.75-60.76, p=0.12). Mean time to treatment failure was 149.7 days and 110.2 days in the pre-emptive group and reactive treatment group, respectively (HR=0.58; 95% CI= 0.26-1.28, p=0.18).. Prophylactic oral minocycline combined with skin care reduced panitumumab-induced acneiform rash without a significant influence on tumor response.

Topics: Acneiform Eruptions; Administration, Oral; Administration, Topical; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antibodies, Monoclonal; Antineoplastic Agents; Cohort Studies; Colorectal Neoplasms; Drug Therapy, Combination; Exanthema; Female; Follow-Up Studies; Humans; Liver Neoplasms; Male; Middle Aged; Minocycline; Neoplasm Staging; Panitumumab; Prognosis; Skin Care

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

Knowledge of the etiology of pyogenic liver and pancreatic abscesses is an important factor in determining the success of combined surgical and antibiotic treatment. Literature shows geographical variations in the prevalence and distribution of causative organisms, and the spread of Klebsiella pneumoniae carbapenemase-producing bacteria is an emerging cause of abdominal infections.. We herein describe two cases of intra-abdominal abscesses due to monomicrobial infection by Klebsiella pneumoniae Sequence Type 258 producing K. pneumoniae carbapenemase 3 (KPC-Kp). In case 1, a 50-year-old HIV-negative Italian woman with chronic pancreatitis showed infection of a pancreatic pseudocystic lesion caused by KPC-Kp. In case 2, a 64-year-old HIV-negative Italian woman with pancreatic neoplasm and liver metastases developed a liver abscess due to KPC after surgery. Both women were admitted to our hospital but to different surgical units. The clonal relationship between the two isolates was investigated by pulsed-field gel electrophoresis (PFGE). In case 2, the patient was already colonized at admission and inter-hospital transmission of the pathogen was presumed. A long-term combination regimen of colistin with tigecycline and percutaneous drainage resulted in full recovery and clearance of the multidrug-resistant (MDR) pathogen.. Timely microbiological diagnosis, the combined use of new and old antibiotics and radiological intervention appeared to be valuable in managing these serious conditions. The emergence and dissemination of MDR organisms is posing an increasing challenge for physicians to develop new therapeutic strategies and control and prevention frameworks.

Topics: Abdominal Abscess; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Colistin; Drug Resistance, Multiple, Bacterial; Electrophoresis, Gel, Pulsed-Field; Female; Humans; Klebsiella Infections; Klebsiella pneumoniae; Liver Neoplasms; Middle Aged; Minocycline; Pancreatic Neoplasms; Pancreatitis, Chronic; Tigecycline

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