hispidulin and Kidney-Neoplasms

In recent years, natural products have increasingly attracted more attention because of their potential anticancer activity and low intrinsic toxicity. Hispidulin is a natural flavonoid with a wide range of biological activities, including anti-inflammatory, antifungal, antiplatelet, anticonvulsant, anti-osteoporotic, and notably anticancer activities. Numerous in vivo and in vitro studies have shown that hispidulin, as a potential anticancer drug, affects cell proliferation, apoptosis, cell cycle, angiogenesis, and metastasis. Moreover, hispidulin exhibits synergistic anti-tumor effects when combined with some common clinical anticancer drugs (e.g., gemcitabine, 5-fluoroucil, sunitinib, temozolomide, and TRAIL). The combination of hispidulin and chemotherapeutic drugs reduces the efflux of chemotherapeutic drugs, enhances the chemosensitivity of cancer cells, and reverses drug resistance. Herein, we outlined the anticancer effects of hispidulin in various cancers and its intracellular molecular targets and related mechanisms of its anticancer activity. Based on the available literature, it can be established that hispidulin has significant potential to become an important complementary medicine for cancer prevention and treatment. However, more in-depth in vitro and in vivo studies should be conducted to support its translation from bench to bedside.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Carcinoma, Renal Cell; Colorectal Neoplasms; Flavones; Flavonoids; Humans; Kidney Neoplasms; Liver Neoplasms; Neoplasms; Pancreatic Neoplasms; Stomach Neoplasms

Hispidulin, a polyphenolic flavonoid extracted from the traditional Chinese medicinal plant S involucrata, exhibits anti-tumor effects in a wide array of human cancer cells, mainly through growth inhibition, apoptosis induction and cell cycle arrest. However, its precise anticancer mechanisms remain unclear. In this study, we investigated the molecular mechanisms that contribute to hispidulin-induced apoptosis of human clear-cell renal cell carcinoma (ccRCC) lines Caki-2 and ACHN. Hispidulin (10, 20 μmol/L) decreased the viability of ccRCC cells in dose- and time-dependent manners without affecting that of normal tubular epithelial cells. Moreover, hispidulin treatment dose-dependently increased the levels of cleaved caspase-8 and caspase-9, but the inhibitors of caspase-8 and caspase-9 only partly abrogated hispidulin-induced apoptosis, suggesting that hispidulin triggered apoptosis via both extrinsic and intrinsic pathways. Moreover, hispidulin treatment significantly inhibited the activity of sphingosine kinase 1 (SphK1) and consequently promoted ceramide accumulation, thus leading to apoptosis of the cancer cells, whereas pretreatment with K6PC-5, an activator of SphK1, or overexpression of SphK1 significantly attenuated the anti-proliferative and pro-apoptotic effects of hispidulin. In addition, hispidulin treatment dose-dependently activated ROS/JNK signaling and led to cell apoptosis. We further demonstrated in Caki-2 xenograft nude mice that injection of hispidulin (20, 40 mg·kg

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Ceramides; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Flavones; Humans; Kidney Neoplasms; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Experimental; Phosphotransferases (Alcohol Group Acceptor); Reactive Oxygen Species; Structure-Activity Relationship; Tumor Cells, Cultured

The aim of the study was to evaluate the effect of the hispidulin, a naturally occurring flavonoid, in combination with a new multi-targeted oral medication, sunitinib on renal cell carcinoma (RCC) cell proliferation in vitro and on tumor growth in vivo. After treatment with hispidulin or sunitinib, either alone or in combination, MTT assay was used to examine cell viability and flow cytometry analysis was employed to examine cell cycle distribution and apoptosis of the RCC cell lines 786-0 and Caki-1. Western blotting was employed to examine the expression of proteins related to pStat3 signaling pathway. Furthermore, a xenograft mouse model was applied to study the antitumor efficacy of sunitinib or hispidulin alone or in combination, with immunohistochemistry to detect expression of proteins related to xenograft growth and angiogenesis. Hispidulin dose-dependently inhibited proliferation and induced apoptosis in both of the tested RCC cell lines when used alone; when combined with sunitinib, relatively low concentration of hispidulin enhanced the antitumor activity of the latter. The antitumor activity of hispidulin and its enhancement of the antitumor activity of sunitinib correlated with the suppression of pStat3 signaling and the consequent downregulation of Bcl-2 and survivin. Moreover, combination of hispidulin and sunitinib inhibited the growth and angiogenesis of xenografts generated from Caki-1 significantly. Immunohistochemistry indicated decreased expression of proteins promoting xenograft growth and angiogenesis after combination treatment of hispidulin and sunitinib. Our results showed that hispidulin, by inhibiting pStat3 signaling, exhibited antitumor activity and the joint use of hispidulin and sunitinib could provide greater antitumor efficacy compared to either drug alone. Therefore, combination treatment with hispidulin and sunitinib might offer a novel therapeutic option for patients with RCC.

Topics: Animals; Antineoplastic Agents; Carcinoma, Renal Cell; Cell Cycle; Cell Line, Tumor; Cell Survival; Drug Synergism; Flavones; Gene Expression Regulation, Neoplastic; Humans; Indoles; Kidney Neoplasms; Male; Mice; Pyrroles; Signal Transduction; STAT3 Transcription Factor; Sunitinib; Xenograft Model Antitumor Assays