Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Matrix metalloproteinases (MMPs) and cyclooxygenase (COX) enzymes play pivotal roles in the metastatic process of colorectal cancers. Inhibition of both MMPs and COX could be an attractive option for the inhibition of cell growth and invasion. Two human colorectal cancer cell lines, LS174T and HT29, were challenged with MMP inhibitor (doxycycline), selective COX-2 inhibitor (NS-398), or a combination of these agents to evaluate cancer cell proliferation and invasion. Dose-dependent growth inhibition was observed in both cell lines when they were treated with a single therapy. These effects were not related to MMP-2 or MMP-9 expression potential of the cell lines. Doxycycline (10 microg/mL) induced G(0)/G(1) arrest, and 20 microg/mL provoked annexin V positivity and up-regulated caspase-3 activity in HT29 cells. However, 20 microg/mL doxycycline caused no distinct apoptotic change in LS174T cells. Although MMP expression was not inhibited by 5 to 10 microg/mL doxycycline or 50 to 100 micromol/L NS-398, MMPs' activities were down-regulated by these concentrations. Cellular invasion was noticed in LS174T cells, but their capacity for invasion was diminished by these inhibitors. The antiproliferative and antiinvasive effects of the combination therapy were more pronounced. Doxycycline (5 microg/mL) with 50 micromol/L NS-398 inhibited cell proliferation and doxycycline (5 microg/mL) with 100 micromol/L NS-398 attenuated MMP expression and activity, as well as capacity for invasion, compared with single therapy. These data suggest that combination therapy consisting of an MMP inhibitor with a COX-2 inhibitor is an attractive approach to the treatment of colorectal cancers. The use of this treatment regimen for chemoprevention or treatment of colorectal cancers should be considered in future clinical trials.
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PMID:Doxycycline inhibits cell proliferation and invasive potential: combination therapy with cyclooxygenase-2 inhibitor in human colorectal cancer cells. 1508 79

Doxycycline (Dc) has been demonstrated to inhibit cell growth and induce apoptosis in tumor cells, although its mechanism of action is not fully understood. The present study demonstrates that apoptosis can be induced in HeLa cells. Western blot data demonstrated that cytochrome c (Cyt c), Smac (the second mitochondria-derived activator of caspase), calpain I, caspase-9, -3 and -8 were involved in the apoptotic process, while the pan caspase inhibitor zVAD-fmk almost completely inhibited Dc-induced apoptosis. We further demonstrated that the release of mitochondrial proteins and the activation of calpains occurred upstream of the caspase cascade, in which caspase-9 was activated in response to the release of Cyt c, that caspase-8 activation was caspase and calpain dependent, and that caspase-3 was activated mainly by caspase-8 and -9. Caspase-8 played important roles in the activation of caspase-3 and induction of apoptosis, whereas the role of the caspase-9 was limited.
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PMID:Mitochondria and calpains mediate caspase-dependent apoptosis induced by doxycycline in HeLa cells. 1659 38

Doxycycline (DOX), a synthetic tetracycline, may have potential utility in the management of cancers and in the treatment of chronic inflammatory diseases due to its role in growth, invasion and metastasis of many tumors, on cell proliferation and as inducer of apoptosis. Some studies established its role in the treatment of lesions induced by mustards, warfare agents causing severe damage with blistering and tissue detachment in exposed areas of the body. In the present study, the effect of Dox was investigated in a human bronchial epithelial cell line. Dox induced a time- and concentration-dependent cell proliferation inhibition, associated with a cell cycle arrest in S phase, a decrease in viability due to apoptosis and necrosis, and cell detachment. This latter was partly correlated with early activation of caspase-3 before detachment, and with mitochondrial alteration. Cell transfection with a Bcl-2 encoding vector showed a decrease both in mitochondrial depolarization and cell detachment. Dox-induced apoptosis included decrease in Bcl-2 expression, increase in Bak expression and caspase-3 and -9 activation but appeared to be p53- and Bax-independent. A better comprehension of the Dox-induced apoptotic pathway could allow to abolish its toxic effects, improving the therapeutic efficiency of Dox.
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PMID:Mechanisms of doxycycline-induced cytotoxicity on human bronchial epithelial cells. 1672 Mar 74

BACKGROUND Inducing mitochondrial dysfunction has been recently demonstrated to be an alternative therapeutic strategy for cancer treatment. Doxycycline is an antibiotic that has been shown to have anti-cancer activities in various cancers by way of targeting mitochondria. In this work, we examined whether doxycycline can be repurposed for glioblastoma treatment. MATERIAL AND METHODS The effects of doxycycline on the growth, survival, and mitochondrial metabolisms of glioblastoma were investigated. The efficacy of a combination of doxycycline with temozolomide was examined using xenograft mouse model in total number of 40 mice. RESULTS Doxycycline targeted glioblastoma cell lines, regardless of their origin, through inhibiting growth and inducing cell death, accompanied by a significant decrease in proliferating cell nuclear antigen (PCNA) and increase in cleaved caspase-3. In addition, doxycycline significantly sensitized glioblastoma cell response to temozolomide in vitro and in vivo. Mechanistically, doxycycline disrupted mitochondrial functions through decreasing mitochondrial membrane potential and mitochondrial respiration. Inducing mitochondrial dysfunctions by using doxycycline led to energy crisis, oxidative stress, and damage as shown by the decreased levels of ATP and the elevated levels of mitochondrial superoxide, intracellular ROS, 8-OHdG, protein carbonylation, and lipid peroxidation. An antioxidant N-acetyl-L-cysteine (NAC) significantly abolished the anti-proliferative and pro-apoptotic effects of doxycycline, demonstrating that doxycycline acts on glioblastoma via inducing oxidative stress. CONCLUSIONS In our study, we show that the antibiotic doxycycline is effective in targeting glioblastoma through inducing mitochondrial dysfunctions and oxidative stress. Our work also demonstrated the importance of mitochondrial metabolism in glioblastoma.
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PMID:Induction of Mitochondrial Dysfunction and Oxidative Damage by Antibiotic Drug Doxycycline Enhances the Responsiveness of Glioblastoma to Chemotherapy. 2884 51

Background and objectives: Cancer stem cells (CSCs) have been implicated in tumor initiation, recurrence, metastatic spread and poor survival in multiple tumor types, breast cancers included. CSCs selectively overexpress key mitochondrial-related proteins and inhibition of mitochondrial function may represent a new potential approach for the eradication of CSCs. Because mitochondria evolved from bacteria, many classes of FDA-approved antibiotics, including doxycycline, actually target mitochondria. Our clinical pilot study aimed to determine whether short-term pre-operative treatment with oral doxycycline results in reduction of CSCs in early breast cancer patients. Methods: Doxycycline was administered orally for 14 days before surgery for a daily dose of 200 mg. Immuno-histochemical analysis of formalin-fixed paraffin-embedded (FFPE) samples from 15 patients, of which 9 were treated with doxycycline and 6 were controls (no treatment), was performed with known biomarkers of "stemness" (CD44, ALDH1), mitochondria (TOMM20), cell proliferation (Ki67, p27), apoptosis (cleaved caspase-3), and neo-angiogenesis (CD31). For each patient, the analysis was performed both on pre-operative specimens (core-biopsies) and surgical specimens. Changes from baseline to post-treatment were assessed with MedCalc 12 (unpaired t-test) and ANOVA. Results: Post-doxycycline tumor samples demonstrated a statistically significant decrease in the stemness marker CD44 (p-value < 0.005), when compared to pre-doxycycline tumor samples. More specifically, CD44 levels were reduced between 17.65 and 66.67%, in 8 out of 9 patients treated with doxycycline. In contrast, only one patient showed a rise in CD44, by 15%. Overall, this represents a positive response rate of nearly 90%. Similar results were also obtained with ALDH1, another marker of stemness. In contrast, markers of mitochondria, proliferation, apoptosis, and neo-angiogenesis, were all similar between the two groups. Conclusions: Quantitative decreases in CD44 and ALDH1 expression are consistent with pre-clinical experiments and suggest that doxycycline can selectively eradicate CSCs in breast cancer patients in vivo. Future studies (with larger numbers of patients) will be conducted to validate these promising pilot studies.
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PMID:Doxycycline, an Inhibitor of Mitochondrial Biogenesis, Effectively Reduces Cancer Stem Cells (CSCs) in Early Breast Cancer Patients: A Clinical Pilot Study. 3036 93