zithromax and Carcinoma--Non-Small-Cell-Lung

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

Although new chemotherapeutic drugs have been applied constantly, their efficacy for non-small cell lung cancer (NSCLC) is still not satisfactory. In recent years, epidemiological investigations have shown that lung cancer may be induced by chronic Chlamydia pneumoniae (Cpn) infection, since stable high titers of Cpn antibodies, especially IgA, are a hallmark of chronic infections. Azithromycin is commonly used for the treatment of Cpn infections; however, there are only few reports regarding the application of azithromycin (A) combined with paclitaxel and cisplatin (TP) for advanced NSCLC. Considering that patients with NSCLC have a higher rate of Cpn infection, we proposed to employ azithromycin for Cpn infection in chemotherapy for advanced NSCLC. The aim of this study was to explore the effects of azithromycin on chemotherapy for NSCLC. A total of 86 patients with stage III-IV NSCLC were randomly divided into TP and ATP groups; the characteristics of patients in the two groups showed no significant differences. The TP group was treated with paclitaxel and cisplatin, and the ATP group was treated with azithromycin combined with TP for at least 4 weeks, followed by evaluation and comparison of efficacy, side effects and patients' quality of life before and after chemotherapy between the two groups. Testing for Cpn infection revealed a significant difference in the case number before and after therapy in the ATP group (P < 0.01) compared with the TP group (P > 0.05), and a statistical difference was observed (P < 0.01) between the ATP and TP groups after treatment. The changes in quality of life of patients after two different chemotherapy regimens were statistically significant (P < 0.05), but there was a significant difference in only cognitive function after treatment. The changes in symptom scores of patients after the two different chemotherapy regimens were statistically significant (P < 0.05), but there was a significant difference in only shortness of breath and cough after treatment. Kaplan-Meier estimate was utilized to describe the survival function of patients in the two groups. The median survival time was 12.0 months for the TP group and 13.0 months for the ATP group. One-year survival rates of the TP and ATP groups were 45.0 and 75.0%, respectively, which were significantly different (P < 0.05). Our study of azithromycin+paclitaxe l+cisplatin on stage III-IV NSCLC patients achieved favorable results in terms of side effects and overall sur

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Azithromycin; Carcinoma, Non-Small-Cell Lung; Chlamydia Infections; Chlamydophila pneumoniae; Cisplatin; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Staging; Paclitaxel; Quality of Life

Cancer cells use autophagy for growth, survival, and cytoprotection from chemotherapy. Therefore, autophagy inhibitors appear to be good candidates for cancer treatment. Our group previously reported that macrolide antibiotics, especially azithromycin (AZM), have potent autophagy inhibitory effects, and combination treatment with tyrosine kinase inhibitors or proteasome inhibitors enhances their anti-cancer activity. In this study, we evaluated the effect of combination therapy with DNA-damaging drugs and AZM in non-small-cell lung cancer (NSCLC) cells. We found that the cytotoxic activities of DNA-damaging drugs, such as doxorubicin (DOX), etoposide, and carboplatin, were enhanced in the presence of AZM in NSCLC cell lines, whereas AZM alone exhibited almost no cytotoxicity. This enhanced cell death was dependent on wild-type-p53 status and autophagosome-forming ability because TP53 knockout (KO) and ATG5-KO cells attenuated AZM-enhanced cytotoxicity. DOX treatment upregulated lysosomal biogenesis by activating TFEB and led to lysosomal membrane damage as assessed by galectin 3 puncta assay and cytoplasmic leakage of lysosomal enzymes. In contrast, AZM treatment blocked autophagy, which resulted in the accumulation of lysosomes/autolysosomes. Thus, the effects of DOX and AZM were integrated into the marked increase in damaged lysosomes/autolysosomes, leading to prominent lysosomal membrane permeabilization (LMP) for apoptosis induction. Our data suggest that concomitant treatment with DNA-damaging drugs and AZM is a promising strategy for NSCLC treatment via pronounced LMP induction.

Topics: A549 Cells; Autophagy; Azithromycin; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Membrane Permeability; Cell Proliferation; Cell Survival; DNA Damage; Drug Synergism; Humans; Lung Neoplasms; Lysosomes; Topoisomerase II Inhibitors