Ursolic acid inhibits colorectal cancer angiogenesis through suppression of multiple signaling pathways

Abstract

Angiogenesis plays a critical role in the development of solid tumors by supplying nutrients and oxygen to support continuous growth of tumor as well as providing an avenue for hematogenous metastasis. Tumor angiogenesis is highly regulated by multiple intracellular signaling transduction cascades such as Hedgehog, STAT3, Akt and p70S6K pathways that are known to malfunction in many types of cancer including colorectal cancer (CRC). Therefore, suppression of tumor angiogenesis through targeting these signaling pathways has become a promising strategy for cancer chemotherapy. Ursolic acid (UA) is a major active compound present in many medicinal herbs that have long been used in China for the clinical treatment of various types of cancer. Although previous studies have demonstrated an antitumor effect for UA, the precise mechanisms of its anti-angiogenic activity are not well understood. To further elucidate the mechanism(s) of the tumorcidal activity of UA, using a CRC mouse xenograft model, chick embryo chorioallantoic membrane (CAM) model, the human colon carcinoma cell line HT-29 and human umbilical vein endothelial cells (HUVECs), in the present study we evaluated the efficacy of UA against tumor growth and angiogenesis in vivo and in vitro and investigated the underlying molecular mechanisms. We found that administration of UA significantly inhibited tumor volume but had no effect on body weight changes in CRC mice, suggesting that UA can suppress colon cancer growth in vivo without noticeable signs of toxicity. In addition, UA treatment reduced intratumoral microvessel density (MVD) in CRC mice, decreased the total number of blood vessels in the CAM model, and dose and time-dependently inhibited the proliferation, migration and tube formation of HUVECs, demonstrating UA's antitumor angiogenesis in vivo and in vitro. Moreover, UA treatment inhibited the expression of critical angiogenic factors, such as VEGF-A and bFGF. Furthermore, UA suppressed the activation of sonic hedgehog (SHH), STAT3, Akt and p70S6K pathways. Collectively, our findings suggest that inhibition of tumor angiogenesis via suppression of multiple signaling pathways might be one of the mechanisms whereby UA can be effective in cancer treatment.

Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α

“…and Prunell avulgaris L. (Cheung et al, 2006;Cheung and Zhang, 2008). It exhibits a broad range of pharmacological effects such as anti-inflammatory, antiviral, antioxidant, and hepatoprotective activities (Feuillolay et al, 2016;Kashyap et al, 2016;Siegel et al, 2016), and has proven to be effective in treating various types of cancers including CRC (Pathak et al, 2007;Prasad et al, 2012;Lin et al, 2013;Kadioglu and Efferth, 2015). Several mechanisms by which UA acts as a chemosensitizer have been proposed, such as pro-apoptosis (Meng et al, 2015) and anti-angiogenesis (Lin et al, 2013).…”

“…It exhibits a broad range of pharmacological effects such as anti-inflammatory, antiviral, antioxidant, and hepatoprotective activities (Feuillolay et al, 2016;Kashyap et al, 2016;Siegel et al, 2016), and has proven to be effective in treating various types of cancers including CRC (Pathak et al, 2007;Prasad et al, 2012;Lin et al, 2013;Kadioglu and Efferth, 2015). Several mechanisms by which UA acts as a chemosensitizer have been proposed, such as pro-apoptosis (Meng et al, 2015) and anti-angiogenesis (Lin et al, 2013). In addition, UA was found to be capable of affecting multiple signaling pathways including nuclear factor-κB (NF-κB) (Prasad et al, 2012), signal transducer and activator of transcription-3 (STAT3) (Pathak et al, 2007), and phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) (Meng et al, 2015), among others.…”

Review on anti-tumor effect of triterpene acid compounds

“…[78,79] Hence, triterpene compounds can inhibit angiogenesis of tumor by inhibiting expression of vascular endothelial growth factor, achieving the goal of antitumor.…”

Therapeutic Interventions Using Ursolic Acid for Cancer Treatment

“…Moreover, immunostaining results demonstrated a decrease in PECAM/CD31 (an endothelial cell marker) in UA-treated tumor sections, whereas the control tumor sections exhibited pronounced vascularity [45]. Lin et al reported that UA treatment inactivates signal transducer and activator of transcription-3 (STAT3), as well as the AKT and sonic hedgehog (SHH) pathways responsible for tumor proliferation, invasion, and angiogenesis [11]. Lin et al used UA to treat human liver cancer (i.e., Hep3B, Huh7, and HA22T cells) cell lines, and found that the expressions of HIF-1, VEGF, and IL-8 significantly reduced in a dose-dependent manner.…”

“…Some of the plants that contain UA include Malus domestica, Origanum majorana, Rosmarinus officinalis, Salvia officinalis, Thymus vulgaris, Eucalyptus, and Coffea arabica, in addition to the outer peel of many different fruits [10]. Ongoing studies have demonstrated that UA is capable of inducing apoptosis, arresting cell cycle progression, inhibiting cellular proliferation, and reducing tumorigenesis in some cancer cells via multiple signaling pathways [2,11]. Bonaccorsi et al found that UA suppresses endogenous reverse transcriptase (RT), an enzyme which regulates cellular proliferation and differentiation, in both melanoma (A375) and anaplastic carcinoma (ARO) cells [12].…”