minocycline and Melanoma

Topics: Anti-Bacterial Agents; Diagnosis, Differential; Humans; Hyperpigmentation; Male; Melanoma; Minocycline; Skin Diseases

A 20-year-old woman presented with a heavily pigmented scar on the left lower abdomen following excision of a benign compound nevus. Reexcision showed an organizing scar with pronounced hemosiderinlike pigment deposition and no residual melanocytic lesion. Results of further histopathologic workup showed positive staining with both Perls stain for iron and Fontana-Masson stain. These findings led to further questioning of the patient, which revealed a history of minocycline therapy--information that had not been provided during her initial evaluation. Hyperpigmented scars may result from minocycline ingestion. We present a review of the literature, with particular regard to the possible mechanisms of minocycline hyperpigmentation and the differential diagnosis of hyperpigmented scars.

Topics: Abdomen; Adult; Anti-Bacterial Agents; Cicatrix; Diagnosis, Differential; Female; Humans; Melanoma; Minocycline; Nevus, Pigmented; Skin Neoplasms

Topics: Apoptosis; Caspases; Cell Line, Tumor; Cytotoxins; Dose-Response Relationship, Drug; Humans; Melanoma; Melanoma, Cutaneous Malignant; Membrane Potential, Mitochondrial; Minocycline; Neoplasm Proteins; Skin Neoplasms

Brain metastases are prevalent in various types of cancer and are often terminal, given the low efficacy of available therapies. Therefore, preventing them is of utmost clinical relevance, and prophylactic treatments are perhaps the most efficient strategy. Here, we show that systemic prophylactic administration of a toll-like receptor (TLR) 9 agonist, CpG-C, is effective against brain metastases. Acute and chronic systemic administration of CpG-C reduced tumor cell seeding and growth in the brain in three tumor models in mice, including metastasis of human and mouse lung cancer, and spontaneous melanoma-derived brain metastasis. Studying mechanisms underlying the therapeutic effects of CpG-C, we found that in the brain, unlike in the periphery, natural killer (NK) cells and monocytes are not involved in controlling metastasis. Next, we demonstrated that the systemically administered CpG-C is taken up by endothelial cells, astrocytes, and microglia, without affecting blood-brain barrier (BBB) integrity and tumor brain extravasation. In vitro assays pointed to microglia, but not astrocytes, as mediators of CpG- C effects through increased tumor killing and phagocytosis, mediated by direct microglia-tumor contact. In vivo, CpG-C-activated microglia displayed elevated mRNA expression levels of apoptosis-inducing and phagocytosis-related genes. Intravital imaging showed that CpG-C-activated microglia cells contact, kill, and phagocytize tumor cells in the early stages of tumor brain invasion more than nonactivated microglia. Blocking in vivo activation of microglia with minocycline, and depletion of microglia with a colony-stimulating factor 1 inhibitor, indicated that microglia mediate the antitumor effects of CpG-C. Overall, the results suggest prophylactic CpG-C treatment as a new intervention against brain metastasis, through an essential activation of microglia.

Topics: Animals; Apoptosis; Brain Neoplasms; Cell Line, Tumor; Colony-Stimulating Factors; Female; Humans; Lung Neoplasms; Male; Melanoma; Mice; Microglia; Minocycline; Oligodeoxyribonucleotides; Phagocytosis; Signal Transduction; Toll-Like Receptor 9

Antibiotics are common drugs with low toxicity but high effectiveness. They have been suggested to be drug candidates for cancer therapy in recent years. Here, we tried to investigate the antitumour effect of tigecycline on malignant melanoma. We showed that tigecycline dramatically inhibited cell proliferation and induced cell cycle arrest at G0/G1 phase. At the same time, tigecycline suppressed cell invasion and migration through preventing epithelial-mesenchymal transition (EMT) process. In addition, tigecycline also significantly blocked tumor growth in vivo. Expression of cell cycle-related proteins were investigated and resulted in downregulation of G1/S checkpoint proteins, such as CDK2 and Cyclin E. However, cyclin-dependent kinase inhibitor 1 (CDKN1A, p21(CIP1/Waf1)) was downregulated after tigecycline treatment, which was not conformed to its conventional function. To explain this, we overexpressed p21 in melanoma cells. We found that p21 overexpression significantly rescued tigecycline-induced cell proliferation inhibition as well as migration and invasion suppression. Taken together, our results revealed that the essential role of p21 in the inhibitory effect of tigecycline on proliferation, migration and invasion of melanoma. Tigecycline might act as a candidate therapeutic drug for treatment of patients suffering from malignant melanoma.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin E; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase Inhibitor p21; Disease Progression; Down-Regulation; Epithelial-Mesenchymal Transition; Female; G1 Phase Cell Cycle Checkpoints; Humans; Melanoma; Melanoma, Cutaneous Malignant; Mice; Mice, Inbred BALB C; Mice, Nude; Minocycline; Neoplasm Invasiveness; Neoplasm Metastasis; Oncogene Proteins; Skin Neoplasms; Tigecycline; Xenograft Model Antitumor Assays

Minocycline, a tetracycline family antibiotic, is known to inhibit microglial activation and proinflammatory cytokine release in animal models. Experimental data show that these immune processes may play a role in epilepto- and ictogenesis. We present the case of a patient with marked reduction in seizure frequency during minocycline therapy with severe symptomatic epilepsy due to an astrocytoma.

Topics: Anticonvulsants; Astrocytoma; Brain Neoplasms; Epilepsy; Humans; Male; Melanoma; Middle Aged; Minocycline; Neoplasms, Multiple Primary; Skin Neoplasms

Tetracyclines were recently found to induce tumour cell death, but the early processes involved in this cytotoxic effect remain unclear.. Viability of human and mouse melanoma cells was determined by MTT assay and flow cytometry. Kinase/protein/caspase activation was measured by Western blotting and mitochondrial membrane potential (DeltaPsi(m)) was analyzed by fluorescence microscopy and flow cytometry.. Human and mouse melanoma cells were treated with doxycycline or minocycline but only doxycycline was cytotoxic. This cell death (apoptosis) in A2058 cells involved activation of caspase-3, -7 and -9 and contributed to inhibition, by doxycycline, of matrix metalloproteinase (MMP) activity and migration of these cells. Doxycycline induced intra-cellular reactive oxygen species (ROS) production, apoptosis signal-regulated kinase 1 (ASK1), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activation at an early stage of treatment and induced mitochondrial cytochrome c release into cytosol and DeltaPsi(m) change during apoptosis. The JNK inhibitor/small interference RNA inhibited doxycycline-induced JNK activation, DeltaPsi(m) change and apoptosis, but did not affect ASK1 activation, suggesting a role of ASK1 for JNK activation in melanoma cell apoptosis. Two ROS scavengers reduced doxycycline-induced JNK and caspase activation, and apoptosis. Taken together, the results suggest the involvement of a ROS-ASK1-JNK pathway in doxycycline-induced melanoma cell apoptosis.. We have shown a promising cytotoxic effect of doxycycline on melanoma cells, have identified ROS and ASK1 as the possible initiators and have demonstrated that JNK activation is necessary for doxycycline-induced melanoma cell apoptosis.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Cytochromes c; Doxycycline; Drug Screening Assays, Antitumor; Free Radical Scavengers; Humans; JNK Mitogen-Activated Protein Kinases; MAP Kinase Kinase Kinase 5; Melanoma; Membrane Potential, Mitochondrial; Mice; Minocycline; p38 Mitogen-Activated Protein Kinases; Reactive Oxygen Species; RNA, Small Interfering; Signal Transduction; Up-Regulation

Bone metastases are a common complication in prostate and breast cancer patients. It leads to extensive morbidity and eventually mortality. Matrix metalloproteinases are implicated in various steps of development of metastasis, through their ability to degrade the extracellular matrix. Increased matrix metalloproteinase activity of tumor cells has been associated with a higher metastatic potential. Inhibitors of metalloproteinases have been shown to effectively reduce or prevent the formation of metastases. The family of tetracyclines is able to inhibit matrix metalloproteinase activity through chelation of the zinc ion at the active site of the enzyme. Using tumor cell lines relevant to bone metastases, i.e. PC-3, MDA-MB-231, Hs696, B16/F1, we showed that tetracycline and derivatives of tetracycline, namely doxycycline and minocycline, also induced cytotoxicity. The effective concentrations are relatively high for plasma, but are clinically achievable in the bone, since tetracyclines are osteotropic. All four bone-metastasizing tumor cells produced and secreted various matrix metalloproteinases. Doxycycline was able to inhibit the activity of 72- and 92-kDa type IV collagenase secreted by bone-metastasizing cells by 79-87%. These characteristics could make tetracycline a unique candidate as a therapeutic agent to prevent bone metastases in cancer patients with a high likelihood for development of bone metastasis. Studies using animal models of experimental bone metastasis will be necessary to confirm this.

Topics: Adenocarcinoma; Animals; Anti-Bacterial Agents; Blotting, Western; Bone Neoplasms; Breast Neoplasms; Cell Survival; Collagenases; Culture Media, Conditioned; Doxycycline; Extracellular Matrix; Gelatinases; Humans; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Melanoma; Metalloendopeptidases; Mice; Minocycline; Prostatic Neoplasms; Protease Inhibitors; Tetracycline; Tetracyclines; Tumor Cells, Cultured

An assessment of the occurrence rate of periungual hyperpigmentation with subungual melanoma (Hutchinson's sign) and periungual hyperpigmentation with other subungual lesions has not been published, although periungual hyperpigmentation with a pigmented streak or other pigmented lesion of the nail has been considered pathognomonic for subungual melanoma for a century. We report a case of minocycline hyperpigmentation presenting as a longitudinal pigmented streak of the nail associated with periungual hyperpigmentation. These pigmentary changes could be mistaken for Hutchinson's sign.

Topics: Adult; Diagnosis, Differential; Female; Humans; Melanoma; Minocycline; Nail Diseases; Pigmentation Disorders; Tetracyclines

The tissue-destructive proteinases of B16-BL6 melanoma cells from C57BL/6 mice and subcellular fractions were examined. Cancer cell organelles were isolated following nitrogen cavitation with the use of sucrose density gradient centrifugation. Serine, cysteine, and metalloproteinases were assayed with the use of radiolabeled proteins and synthetic substrates. Tumor-induced red blood cell lysis was quantitated by measurement of the release of isotope from 59Fe-labeled red blood cells (RBC) cocultivated with melanoma cells; the RBC were from Wistar rats. Enzyme inhibitors with specificity toward different classes of proteinases were used in the above assays to categorize the enzymes responsible for substrate degradation. Results indicated that intact melanoma cells, cell organelles, and cytosol contain proteinases that can degrade collagen and gelatin and lyse normal RBC. Melanoma plasma membranes are highly enriched in collagenase, gelatinase, cysteine proteinase, plasminogen activator, and cytolytic activity. The inhibition of tumor collagenolytic, gelatinolytic, and cytolytic activities by EDTA and 1,10-phenanthroline but not by diisopropyl fluorophosphate and N alpha-p-tosyl-L-lysine chloromethyl ketone indicates that metalloproteinases are the active enzymes in these assays. Minocycline, a synthetic tetracycline with demonstrable inhibitory activity with other mammalian collagenases, also inhibited melanoma collagenolytic and cytolytic activities.

Topics: Animals; Cell Membrane; Cysteine Endopeptidases; Endopeptidases; Erythrocytes; Female; Gelatinases; Melanoma; Mice; Mice, Inbred C57BL; Microbial Collagenase; Minocycline; Pepsin A; Serine Endopeptidases; Tetracyclines