Enhanced antitumor and anti-angiogenic effects of metronomic Vinorelbine combined with Endostar on Lewis lung carcinoma

Abstract

BackgroundConventional chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC) however it increases therapeutic resistance. In contrast, metronomic chemotherapy (MET) is based on frequent drug administration at lower doses, resulting in inhibition of neovascularization and induction of tumor dormancy. This study aims to evaluate the inhibitory effects, adverse events, and potential mechanisms of MET Vinorelbine (NVB) combined with an angiogenesis inhibitor (Endostar).MethodsCirculating endothelial progenitor cells (CEPs), apoptosis rate, expression of CD31, vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1α) were determined using flow cytometry, western blot analysis, immunofluorescence staining and Enzyme-linked immunosorbent assay (ELISA) analysis. And some animals were also observed using micro fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) to identify changes by comparing SUVmax values. In addition, white blood cell (WBC) counts and H&E-stained sections of liver, lungs, kidney, and heart were performed in order to monitor toxicity assessments.ResultsWe found that treatment with MET NVB + Endo was most effective in inhibiting tumor growth, decreasing expression of CD31, VEGF, HIF-1α, and CEPs, and reducing side effects, inducing apoptosis, such as expression of Bcl-2, Bax and caspase-3. Administration with a maximum tolerated dose of NVB combined with Endostar (MTD NVB + Endo) demonstrated similar anti-tumor effects, including changes in glucose metabolism with micro fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) imaging, however angiogenesis was not inhibited. Compared with either agent alone, the combination of drugs resulted in better anti-tumor effects.ConclusionThese results indicated that MET NVB combined with Endo significantly enhanced anti-tumor and anti-angiogenic responses without overt toxicity in a xenograft model of human lung cancer.

Tumor Angiogenesis and Anti-Angiogenic Strategies for Cancer Treatment

“…Metronomic chemotherapy comprises the frequent administration of drugs at lower doses to inhibit neovascularization and induce tumor dormancy. The study was performed on a xenograft model of human lung cancer and it proved the efficiency of this strategy for anti-tumoral purposes, as it led to enhanced anti-tumor and anti-angiogenic effects without causing toxicity compared with either agent alone [136]. Apatinib is another anti-angiogenic agent that was assessed for its efficacy and safety in combination with an oral etoposide for the treatment of platinum-resistant or platinum-refractory ovarian cancer.…”

An update on angiogenesis modulators with a potential therapeutic role

“…Also, Qin RS et al (2018) have successfully used metronomic therapy (low dose -high frequency) with Vinorelbine (NVB) administered with a known angiogenesis inhibitor, Endostar, to treat animal subjects with non-small cell lung cancer [35]. In the same study, they observed a significant decrease of HIF-1 as well as VEGF and CD31 associated with a decrease in tumour development as assessed by micro fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) [35]. However, the authors did not report a reduction in cancerassociated angiogenesis.…”

“…Studies conducted in-vitro in human breast cancer cell line (MDA-MB-231) have revealed that analogues of the CJ-3k antagonist have an efficient anti-HIF activity suggesting that they might be effective as anticancer pharmacological agents [34]. Also, Qin RS et al (2018) have successfully used metronomic therapy (low dose -high frequency) with Vinorelbine (NVB) administered with a known angiogenesis inhibitor, Endostar, to treat animal subjects with non-small cell lung cancer [35]. In the same study, they observed a significant decrease of HIF-1 as well as VEGF and CD31 associated with a decrease in tumour development as assessed by micro fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) [35].…”

“…This observation would suggest that while VEGF/HIF-1 are important for tumour growth the above mentioned metronomic therapy might have a direct anti-tumoral effect unrelated to the theoretical anti-angiogenic potential of the proposed therapy. Alternatively, one could speculate that the anti-tumoral effect is much more rapid than the anti-angiogenic effect of Vinorelbine combined with Endostar [35].…”

“…In conclusion, modulation of angiogenesis is possible and new factors have shown promising results in experiments conducted in vitro and in vivo. Often times the authors record puzzling effects such as the anti-tumoral effect of combination Vinorelbine and an anti-angiogenic agent such as Endostar in subjects with non-small cell lung carcinoma in which cancer-associated angiogenesis was not affected [35]. Other studies have revealed important physio-pathological mechanisms which must be further investigated such as the role of Tie-2 in impermeabilization of blood vessels [49].…”