minocycline and Neoplasm-Metastasis

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Metastasis is a major cause of CRC recurrence and mortality. Several antibiotic drugs have been reported to exert potential anticancer activities, however, whether and how the tetracycline antibiotic minocycline exhibit tumor suppressive effect on CRC remains unknown. Here, we found that minocycline markedly inhibits the epithelial-mesenchymal transition (EMT) process and metastasis of CRC cells both

Topics: Anti-Bacterial Agents; Cell Line, Tumor; Cell Movement; Colorectal Neoplasms; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Minocycline; Neoplasm Metastasis; STAT3 Transcription Factor

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

The antiangiogenic, antitumoural and antimetastatic effects of two novel sulphonic derivatives of distamycin A, PNU145156E and PNU153429, were studied in a Kaposi's sarcoma-like tumour model obtained by injecting nude mice with cells releasing extracellular HIV-Tat protein, derived from a tumour which developed in a BK virus/tat transgenic mouse. Both PNU145156E and PNU153429 were administered intraperitoneally every fourth day for three weeks at doses of 100 or 50 mg/kg of body weight respectively, starting one day after injecting the tumour cells. Both drugs delayed tumour growth in nude mice, preventing neovascularization induced by the Tat protein. PNU153429 also significantly reduced the number and size of spontaneous tumour metastases. Both effects on tumour growth and metastases were augmented by treating simultaneously nude mice with 7.5 mg/kg of body weight of minocycline given per os daily for four weeks starting four days after injecting the tumour cells. Neither acute nor chronic toxic side-effects were observed during the life span of treated nude mice. Due to their antiangiogenic and anti-Tat effects, these drugs are promising for the treatment of Kaposi's sarcoma in AIDS patients.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Distamycins; Drug Screening Assays, Antitumor; Female; Gene Products, tat; Genes, tat; HIV-1; Male; Mice; Mice, Nude; Mice, Transgenic; Minocycline; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Transplantation; Neovascularization, Pathologic; Sarcoma, Kaposi; tat Gene Products, Human Immunodeficiency Virus; Transfection

Topics: Animals; Anti-Bacterial Agents; Carcinoma, Renal Cell; Endothelial Growth Factors; Fibroblast Growth Factor 2; Kidney Neoplasms; Lung Neoplasms; Lymphokines; Matrix Metalloproteinase Inhibitors; Metalloendopeptidases; Mice; Minocycline; Neoplasm Invasiveness; Neoplasm Metastasis; Protease Inhibitors; Statistics, Nonparametric; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Minimal residual tumor or minimal residual metastatic disease is a major clinical problem for detection and treatment. The purpose of the study was to develop a model system to detect the occurrence and response to therapy of minimal residual tumor in distant organs.. Animals bearing subcutaneously growing established (day 8) murine EMT-6 mammary carcinoma tumors were treated with single doses of the antitumor alkylating agents, cyclophosphamide, melphalan, cis-diamminedichloroplatinum(II) (CDDP) or thiotepa. Tumors, livers, lungs, brain, spleen, blood and bone marrow were collected from the animals 24 h later and single-cell suspensions of these tissues were plated and cultured under conditions suitable for tumor cell colony growth.. Tumor cell colonies grew from each of the tissues with varying frequency ranging from about 6 x 10(3) tumor cell colonies per 10(6) cells plated from the liver, to about 2 tumor cell colonies per 10(6) cells plated from the brain. There was a wide range of sensitivity, spanning 2- to 3-log of the tumor cells, to the antitumor alkylating agents depending upon the tissue in which the tumor cells were located. Tumor cells in the circulating blood were most sensitive to the antitumor alkylating agents with no colony growth after treatment of the animals with any of the four drugs tested. The primary tumor growing subcutaneously in the upper hindleg of the animals was also relatively sensitive to each of the four antitumor alkylating agents tested. EMT-6 tumor cells in the spleen were very sensitive to cyclophosphamide, moderately sensitive to melphalan, less sensitive to CDDP and least sensitive to thiotepa. EMT-6 tumor cells in the bone marrow were moderately sensitive to cyclophosphamide, melphalan and thiotepa but less sensitive to CDDP. EMT-6 tumor cells in the lungs were relatively sensitive to thiotepa, moderately sensitive to cyclophosphamide and CDDP and least sensitive to melphalan. EMT-6 tumor cells in the liver or brain were least responsive to treatment of the host with any of the four antitumor alkylating agents tested.. Treatment of the tumor-bearing animals with the antiangiogenic combination, TNP-470/minocycline, markedly increased EMT-6 tumor cell killing by cyclophosphamide in the liver, lungs and bone marrow. These results indicate that location within the host is an important determinant in the response of tumor cells to therapy.

Topics: Animals; Antineoplastic Agents, Alkylating; Cisplatin; Cyclohexanes; Cyclophosphamide; Female; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Minocycline; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasm, Residual; O-(Chloroacetylcarbamoyl)fumagillol; Sesquiterpenes; Tissue Distribution