zithromax and Glioblastoma

The resistance, plasticity and heterogeneity of cancer cells, including glioblastoma (GB) cells, have prompted the investigation of various agents for possible adjuncts and alternatives to existing therapies. This includes a macrolide antibiotic, azithromycin (AZI). It possesses intriguing anticancer properties in a range of cancer models in vitro, such as antiproliferative, pro-apoptotic, anti-autophagy and anti-angiogenic effects. In fact, AZI is renowned for its ability to eradicate cancer stem cells by inhibiting mitochondrial biogenesis and respiration. AZI-containing regimens in cancer patients for different purposes have shown favourable (i.e., attributed to its antibacterial activity) and unfavourable outcomes. Whilst its direct anticancer effects have yet to be clinically proven. To that end, this review provides a summary of AZI anticancer studies and delineates its potential activities in overcoming the challenges of GB.

Topics: Anti-Bacterial Agents; Azithromycin; Glioblastoma; Humans

Pharmacological targeting aberrant activation of epidermal growth factor receptor tyrosine kinase signaling is an established approach to treating lung adenocarcinoma. Osimertinib is a tyrosine kinase approved and effective in treating lung adenocarcinomas that have one of several common activating mutations in epidermal growth factor receptor. The emergence of resistance to osimertinib after a year or two is the rule. We developed a five-drug adjuvant regimen designed to increase osimertinib's growth inhibition and thereby delay the development of resistance. Areas of Uncertainty: Although the assembled preclinical data is strong, preclinical data and the following clinical trial results can be discrepant. The safety of OPALS drugs when used individually is excellent. We have no data from humans on their tolerability when used as an ensemble. That there is no data from the individual drugs to suspect problematic interaction does not exclude the possibility.. All relevant PubMed.org articles on the OPALS drugs and corresponding pathophysiology of lung adenocarcinoma and glioblastoma were reviewed. Therapeutic Opinion: The five drugs of OPALS are in wide use in general medicine for non-oncology indications. OPALS uses the anti-protozoal drug pyrimethamine, the antihistamine cyproheptadine, the antibiotic azithromycin, the antihistamine loratadine, and the potassium sparing diuretic spironolactone. We show how these inexpensive and generically available drugs intersect with and inhibit lung adenocarcinoma growth drive. We also review data showing that both OPALS adjuvant drugs and osimertinib have data showing they may be active in suppressing glioblastoma growth.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Animals; Azithromycin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Chemotherapy, Adjuvant; Cyproheptadine; Drug Repositioning; Drug Resistance, Neoplasm; ErbB Receptors; Glioblastoma; Humans; Loratadine; Lung Neoplasms; Mice; Neoplasm Metastasis; Pyrimethamine; Spironolactone

The poor outcomes in glioblastoma (GBM) necessitate new treatments. As GBM is highly vascularized and its growth is largely dependent on angiogenesis, angiogenesis inhibitors have been hotly evaluated in clinical trials for GBM treatment for the last decade. In line with these efforts, our work reveals that azithromycin, a clinically available antibiotic, is a novel angiogenesis inhibitor. Azithromycin inhibits vessel structure formation on Matrigel of GBM-derived endothelial cell (ECs) and other types of ECs. Time course analysis shows that azithromycin interferes with the early stage of angiogenesis. Azithromycin also inhibits GBM-derived EC adhesion, growth and survival but not migration. The transgenic zebrafish Tg (fli1a: EGFP) model clearly shows that azithromycin inhibits angiogenesis in vivo. Of note, azithromycin at non-toxic dose inhibits GBM growth in mice and increases overall survival, and furthermore, this is associated with angiogenesis inhibition. Mechanism studies show that azithromycin decreases mitochondrial respiration by suppressing the activity of multiple complexes, leading to ATP reduction, oxidative stress and damage. In addition, oxidative stress induced by azithromycin is through thiol redox-mediated pathways. Our work demonstrates the anti-angiogenic activity of azithromycin via inducing mitochondrial dysfunction and oxidative stress. Our pre-clinical evidence provides a rationale for initiating clinical trials using azithromycin in combination with standard-of-care drugs for GBM patients.

Topics: Angiogenesis Inhibitors; Animals; Azithromycin; Brain Neoplasms; Cell Line, Tumor; Glioblastoma; Mice; Mitochondria; Neovascularization, Pathologic; Oxidative Stress; Zebrafish

Previous studies had reported on the cytotoxic activities of generic antibiotics such as doxycycline (DOXY) and azithromycin (AZI) in multiple types of human cancers. Given that resistance to standard anti-glioblastoma multiforme (GBM) drug [temozolomide (TMZ)] is common and inevitable, alternative candidates are greatly needed.. The present study was undertaken to explore the cytotoxicity and anticancer effects of DOXY and AZI on human GBM U87 cells via 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), Hoechst, Annexin V-FITC/PI, and clonogenic assays. CompuSyn software was used to determine the combination index (CI) for DOXY+AZI.. Individual treatment with DOXY and AZI decreased U87 cell viability in dose- and time-dependent, and quantitatively comparable to TMZ. Nevertheless, combinations of both antibiotics evidenced antagonistic behaviour in U87 cells. Increased apoptotic event was also observed with the individual treatment of DOXY and AZI. Furthermore, the proliferative and clonogenic capability of 21-day survived U87 cells was completely terminated by DOXY and AZI, but not TMZ.. The antiproliferative and apoptosis-inducing activity exhibited by both antibiotics against U87 cells demonstrates their potential as a likely alternative to combat GBM. It would be interesting to find out more about their molecular players and cytotoxic effects in different types of GBM cells, including glioma stem cells (GSCs).

Topics: Antibiotics, Antineoplastic; Azithromycin; Cell Line, Tumor; Cytotoxins; Doxycycline; Drug Therapy, Combination; Glioblastoma; Humans