Azithromycin enhances the favorable results of paclitaxel and cisplatin in patients with advanced non-small cell lung cancer

Chu, De-Jie; Yao, Difei; Zhuang, Yan; Hong, Yuan; Zhu, Xiaojuan; Fang, Zhenjian; Yu, Jae Kook; Yu, Zhongwei

doi:10.4238/2014.april.14.8

Cited by 32 publications

(31 citation statements)

References 14 publications

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“…Finally, recent clinical trials with doxycycline and azithromycin (intended to treat cancer-associated infections, but not cancer cells) both show positive therapeutic effects in cancer patients, although their selective effects on eradicating cancer stem cells were not yet known or appreciated [23-26]. These trials were performed on advanced or treatment-resistant patients with B-cell lymphoma (doxycycline) or lung cancer (azithromycin), respectively [23-26].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…These trials were performed on advanced or treatment-resistant patients with B-cell lymphoma (doxycycline) or lung cancer (azithromycin), respectively [23-26]. For example, in lung cancers, azithromycin significantly increased 1-year patient survival from 45% to 75%, an ~1.7-fold increase [26]. Interestingly, it was noted that even lymphoma patients that were “bacteria-free” benefited from only a 3-week course of doxycycline therapy, and showed complete remission of the disease [27].…”

Section: Discussionmentioning

confidence: 99%

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Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease

et al. 2015

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Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of “stemness”, independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point – a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known “side-effect”, which could be harnessed instead as a “therapeutic effect”. Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease

et al. 2015

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“…With the exception of its antimicrobial activity, azithromycin exerts anti-inflammatory effects by suppressing the secretion of pro-inflammatory cytokines, including interluekin-8 (15). Previously, azithromycin was reported to inhibit the proliferation of cervical and gastric tumor cells (16,17) and enhance the effects of chemotherapy in NSCLC, however little is known about the underlying mechanisms of its anti-cancer activities (18). …”

Section: Introductionmentioning

confidence: 99%

Azithromycin effectively inhibits tumor angiogenesis by suppressing vascular endothelial growth factor receptor 2-mediated signaling pathways in lung cancer

Huang

et al. 2017

Oncology Letters

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Tumor angiogenesis is essential during lung cancer development and targeting angiogenesis may possess a potential therapeutic value. The present study demonstrates that azithromycin, a Food and Drug Administration-approved antibiotic drug, is a novel tumor angiogenesis inhibitor. Azithromycin inhibits capillary network formation of human lung tumor associated-endothelial cells (HLT-ECs) in vitro and in vivo. It significantly inhibits HLT-EC adhesion and vascular endothelial growth factor (VEGF)-induced proliferation of HLT-ECs in a dose-dependent manner without affecting migration. In addition, azithromycin induces apoptosis of HLT-ECs even in the presence of VEGF. Notably, azithromycin inhibits proliferation and induces apoptosis in multiple lung cancer cell lines to a significantly reduced extent compared with in HLT-ECs, suggesting that HLT-ECs are more susceptible to azithromycin treatment. In a lung tumor xenograft model, azithromycin significantly inhibits tumor growth and its anti-tumor activities are achieved by suppressing angiogenesis. Notably, the inhibitory effects of azithromycin on angiogenesis are associated with its ability to suppress VEGF-induced activation of VEGF receptor 2 (VEGFR2), phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), focal adhesion kinase, and disruption of focal adhesion assembly and actin stress fiber formation in HLT-ECs. The present study identifies that azithromycin targets VEGFR2-mediated focal adhesion and PI3K/Akt signaling pathways in HLT-ECs, leading to the suppression of angiogenesis and lung tumor growth.

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“…H460 cells or stem cells were seeded on 96-well plates at a density of 5000 cells per well, suspended in 100 mL culture medium, and allowed to adhere for 24 h. Subsequently, T. chinensis var. or cisplatin (positive control) (Sigma-Aldrich, St. Louis, MO, USA) (Chu et al, 2014) was added to the wells at varying concentrations and the cells were cultured for 72 h; an untreated control group was also included. CCK-8 solution (10 mL) was added to each well and the plates were incubated for 2 h. The absorbance (optical density at 490 nm) of the cultures was determined using a microplate reader (Bio-Rad, Hercules, CA, USA).…”

Section: Cell Counting Kit-8 (Cck-8) Cell Survival Assaymentioning

confidence: 99%

Reversal of cisplatin resistance in non-small cell lung cancer stem cells by Taxus chinensis var.

Jiang

Guo

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Drug resistance in cells is a major impedance to successful treatment of lung cancer. Taxus chinensis var. inhibits the growth of tumor cells and promotes the synthesis of interleukins 1 and 2 and tumor necrosis factor, enhancing immune function. In this study, T. chinensis var.-induced cell death was analyzed in lung cancer cells (H460) enriched for stem cell growth in a defined serum-free medium. Taxus-treated stem cells were also analyzed for Rhodamine 123 (Rh-123) expression by flow cytometry, and used as a standard functional indicator of MDR. The molecular basis of T. chinensis var.-mediated drug resistance was established by real-time PCR analysis of ABCC1, ABCB1, and lung resistance-related protein (LRP) mRNA, and western blot analysis of MRP1, MDR1, and LRP. Our results revealed that stem cells treated with higher doses of T. chinensis var. showed significantly lower growth inhibition rates than did H460 cells (P < 0.05). The growth of stem and H460 cells treated with a combination of T. chinensis var. and cisplatin was also significantly inhibited (P < 0.05). Rh-123

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Azithromycin enhances the favorable results of paclitaxel and cisplatin in patients with advanced non-small cell lung cancer

Cited by 32 publications

References 14 publications

Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease

Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease

Azithromycin effectively inhibits tumor angiogenesis by suppressing vascular endothelial growth factor receptor 2-mediated signaling pathways in lung cancer

Reversal of cisplatin resistance in non-small cell lung cancer stem cells by Taxus chinensis var.

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