It is well established that angiogenesis is the process of formation of new capillaries from pre-existing blood vessels. It is a complex process, involving both pro- and anti-angiogenic factors, and plays a significant role in physiological and pathophysiological processes such as embryonic development, atherosclerosis, post-ischemic vascularization of the myocardium, tumor growth and metastasis, rheumatoid arthritis etc. This is the first report of zinc oxide (ZnO) nanoflowers that show significant pro-angiogenic properties (formation of new capillaries from pre-existing blood vessels), observed by in vitro and in vivo angiogenesis assays. The egg yolk angiogenesis assay using ZnO nanoflowers indicates the presence of matured blood vessels formation. Additionally, it helps to promote endothelial cell (EA.hy926 cells) migration in wound healing assays. Formation of reactive oxygen species (ROS), especially hydrogen peroxide (H(2)O(2))-a redox signaling molecule, might be the plausible mechanism for nanoflower-based angiogenesis. Angiogenesis by nanoflowers may provide the basis for the future development of new alternative therapeutic treatment strategies for cardiovascular and ischemic diseases, where angiogenesis plays a significant role.
Vascular endothelial growth factor/vascular permeability factor (VEGF/VPF or VEGF-A) is a pivotal driver of cancer angiogenesis that is a central therapeutic target in treatment of malignancy. However, little work has been devoted to investigating functions of VEGF that are independent of its pro-angiogenic activity. Here we report that VEGF produced by tumor cells acts in an autocrine manner to promote cell growth through interaction with the VEGF receptor neuropilin-1 (NRP-1). Reducing VEGF expression by tumor cells induced a differentiated phenotype in vitro and inhibited tumor-forming capacity in vivo independent of effects on angiogenesis. Autocrine activation of tumor cell growth was dependent on signaling through NRP-1 and Ras was determined to a critical effector signaling molecule downstream of NRP-1. Our findings define a novel function for VEGF in de-differentiation of tumor cells, expanding its role in cancer beyond its known pro-angiogenic function.
Angiogenesis is a hallmark of tumor development and metastatic progression, and antiangiogenic drugs targeting the VEGF pathway have shown to decrease the disease progression in cancer patients. In this study, we have analyzed the anti-proliferative and anti-angiogenic property of plumbagin in cisplatin sensitive, BRCA2 deficient, PEO-1 and cisplatin resistant, BRCA2 proficient PEO-4 ovarian cancer cells. Both PEO-1 and PEO-4 ovarian cancer cells are sensitive to plumbagin irrespective of BRCA2 status in both normoxia and hypoxia. Importantly, plumbagin treatment effectively inhibits VEGF-A and Glut-1 in PEO-1 and PEO-4 ovarian cancer cells. We have also analyzed the p53 mutant, cisplatin resistant, and BRCA2 proficient OVCAR-5 cells. Plumbagin challenge also restricts the VEGF induced pro-angiogenenic signaling in HUVECs and subsequently endothelial cell proliferation. In addition, we observe a significant effect on tumor regression among OVCAR-5 tumor-bearing mice treated with plumbagin, which is associated with significant inhibition of Ki67 and vWF expressions. Plumbagin also significantly reduces CD31 expression in an ear angiogenesis assay. Collectively, our studies indicate that plumbagin, as an anti-cancer agent disrupts growth of ovarian cancer cells through the inhibition of proliferation as well as angiogenesis.
It is a challenge to develop a universal single drug that can treat breast cancer at single or multiple-stage complications, yet remains nontoxic to normal cells. The challenge is even greater when breast cancer-specific estrogen-based drugs are being developed which cannot act against multi-staged breast cancer complications owing to cells’ differential ER expression status and their possession of drug-resistant and metastatic phenotypes. We report here the development of a first cationic lipid-conjugated estrogenic derivative (ESC8) that kills breast cancer cells independent of their estrogen receptor (ER) expression status. This ESC8 molecule apparently is nontoxic to normal breast epithelial cells, as well as to other non-cancer cells. ESC8 induces apoptosis through an intrinsic pathway in ER-negative MDA-MB-231 cells. In addition, ESC8-treatment induces autophagy in these cells by interfering with the mTOR activity. This is the first example of an estrogen structure-based molecule that co-induces apoptosis and autophagy in breast cancer cells. Further in vivo study confirms the role of this molecule in tumor regression. Together, our results open new perspective of breast cancer chemotherapy through a single agent, which could provide the therapeutic benefit across all stages of breast cancer.
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