New application of an old drug: Antitumor activity and mechanisms of doxycycline in small cell lung cancer

Abstract

Abstract. Small cell lung cancer (SCLC) remains one of the most aggressive tumors with a poor prognosis. The clinical outcome of SCLC patients has reached its plateau with the existing standard treatment and thus new therapies are urgently required. Accumulating evidences have indicated that doxycycline, a commonly used antibiotic, has antitumor activity against several malignancies. However, whether doxycycline has antitumor activity in SCLC and its underlying mechanisms remain unclear. Our investigation demonstrated that doxycycline could significantly inhibit the proliferation and colony formulation of SCLC cells (p<0.05). Furthermore, both Hoechst 33258 dye staining and TUNEL assays indicated that doxycycline could induce remarkable apoptosis of H446 cells in a concentration-dependent manner. RT-PCR and western blot assays proved that apoptosis induction effect of doxycycline was achieved via inducing the expression of caspase-3 and bax, as well as attenuating the expression of survivin and bcl-2. Moreover, the wound healing assay and Transwell assay indicated that doxycycline could significantly suppress the migration and invasion of H446 cells in a concentration-dependent manner (p<0.05). ELISA assay proved that the inhibitory effect of doxycycline on the migration and invasion of H446 cells was achieved via decreasing the secretion of MMP-2, MMP-9 and VEGF, as well as increasing the secretion of TIMP-2. Taken together, doxycycline dose-dependently suppressed the proliferation, colony formulation, migration and invasion of SCLC cells, as well as induced apoptosis. These findings encourage further investigations on the potential of doxycycline as a candidate drug for the treatment of SCLC. IntroductionLung cancer remains the most common cause of cancer-related death worldwide, and was responsible for 1.56 million deaths annually, as of 2012 (1). The main primary types are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Compared with NSCLC, SCLC has a more aggressive behavior due to its higher proliferative index and tends to spread in its early stages. Combination chemotherapy, generally platinumbased plus etoposide or irinotecan, is the mainstay first-line treatment for metastatic SCLC patients (2,3). Despite the initial sensitivity, the long-term outcomes of the majority of SCLC patients remain poor due to early relapse and acquired resistance (2). In addition, the vast majority of patients with SCLC fail to respond to tyrosine-kinase inhibitors against the epidermal growth factor receptor (EGFR) (4). Except for topotecan, few treatment options then remain (2,5,6). Therefore, it is urgent to develop novel and more effective therapeutic drugs for the treatment of SCLC patients. Doxycycline (DOXY) is a member of the tetracycline family of antibiotics in widespread clinical use. Accumulating evidence has suggested that doxycycline has antitumor activity against several kinds of malignancies. It has been reported that doxycycline has anti-metastatic activity and cytotoxicity in melanoma ...

Double‐blind placebo‐controlled randomized clinical trial evaluating doxycycline effects on chemotherapy‐induced oral mucositis

“…5,25 Tetracycline derivatives are recognized as potent MMP inhibi- 12,17,26,27 rheumatoid arthritis, metabolic bone diseases, 16 lung disease or even as an antitumor agent in lung cancer. 16,28 According to previous studies, [13][14][15][16][17][18][19][20] the most common subantimicrobial dose of doxycycline used is 40 mg/d, but in our country the presentation of 20 mg is unavailable, so we decided to use a low dose of doxycycline (50 mg, once daily). In this respect, a daily dose of 50 mg has proved to be effective in treating Grave′s orbitopathy 11 and abdominal aneurysm.…”

“…Recently, another subantimicrobial dose formulation of doxycycline has been approved by the U.S. FDA for rosacea . Doxycycline effectiveness has been described in other MMP‐related disorders, such as cardiovascular aortic diseases (atherosclerosis, aortic aneurysms and myocardial infarction), rheumatoid arthritis, metabolic bone diseases, lung disease or even as an antitumor agent in lung cancer …”

In Vitro Drug Release and Biocatalysis from pH-Responsive Gold Nanoparticles Synthesized Using Doxycycline

“…Along with its antimicrobial effects, 35 its anticancer activities have also been reported previously. 36,37 It has both capabilities of reducing and stabilizing the AuNPs. It can also play the role of a linker to attach the anticancer drug doxorubicin.…”

α-Hederin Saponin Augments the Chemopreventive Effect of Cisplatin against Ehrlich Tumors and Bioinformatic Approach Identifying the Role of SDF1/CXCR4/p-AKT-1/NFκB Signaling

“…CXCR4 and its ligand SDF1 have previously been identified as important metastatic contributors in a variety of malignancies [ 51 , 52 ]. CXCR4 overexpression is linked to enhanced vascular endothelial growth factor recruitment, cancer cell proliferation, and metastasis [ 53 , 54 ]. Moreover, CXCR4 suppression has also been associated with increased tumor cell death [ 54 , 55 ].…”