Angiogenesis: Managing the Culprits behind Tumorigenesis and Metastasis

Deregulated angiogenesis has been identified as a key contributor in a number of pathological conditions including cancer. It is a complex process, which involves highly regulated interaction of multiple signalling molecules. The pro-angiogenic signalling molecule, vascular endothelial growth factor (VEGF) and its cognate receptor 2 (VEGFR-2), which is often highly expressed in majority of human cancers, plays a central role in tumour angiogenesis. Owing to the importance of tumour vasculature in carcinogenesis, tumour blood vessels have emerged as an excellent therapeutic target. The anti-angiogenic therapies have been shown to arrest growth of solid tumours through multiple mechanisms, halting the expansion of tumour vasculature and transient normalization of tumour vasculature which help in the improvement of blood flow resulting in more uniform delivery of cytotoxic agents to the core of tumour mass. This also helps in reduction of hypoxia and interstitial pressure leading to reduced chemotherapy resistance and more uniform delivery of cytotoxic agents at the targeted site. Thus, complimentary combination of different agents that target multiple molecules in the angiogenic cascade may optimize inhibition of angiogenesis and improve clinical benefit in the cancer patients. This review provides an update on the current trend in exploitation of angiogenesis pathways as a strategy in the treatment of cancer.Ashwaq H. S. Yehya is funded by TWAS (The Academy of Sciences for the Developing World, Italy). Chern Ein Oon is supported by L’Oréal-UNESCO for Women in Science National Fellowship (304/CIPPM/650806/L117) and MAKNA Cancer Research Award (304/CIPPM/650859/M122)

Broad spectrum targeting of tumor vasculature by medicinal plants: An updated review

Deregulated angiogenesis plays a central role in the development and metastasis of solid cancers. Tumor vasculature expressing a variety of biomarkers offers some novel therapeutic options which can be selectively targeted with anti-angiogenic agents without significantly affecting the normal vasculature. However, anti-angiogenic agents currently available commercially (synthetic compounds and humanized monoclonal antibodies) have been designed to target specific molecular markers within the cell signalling networks in addition to being expensive as well as toxic. Therefore, it is highly desirable to search for new therapeutic moieties which can simultaneously treat multiple aberrant pathways yet being less toxic and inexpensive. Several studies have highlighted that medicinal plants either as crude extracts or as pure isolated compounds can meet these criteria. The unique combination of different classes of phytochemicals present in plant extracts have been shown simultaneously to target multiple abnormal pathways in the tumor angiogenic cascade thus arresting growth of tumor cells at various stages. In addition, these phytochemicals have health promoting benefits making them ideal candidates to be pursued for drug development. The current review provides an update on the broad spectrum anti-angiogenic activities of different classes of phytochemicals present in the medicinal plants. Although preclinical studies have shown promising results, further studies are required to explore the in-depth molecular mechanisms responsible for the observed pharmacological activities and to test the efficacy of isolated compounds or standardised extracts in properly designed experiments. In addition, long term toxicity studies and data on interaction with other drugs are also required to establish the safety profile of extracts before the commencement of clinical trials.Ashwaq, H. S. Yehya and Muhammad Asif were supported by TWAS (The Academy of Sciences for the Developing World, Italy) and IPS USM (USM fellowship) respectively and NKEA Grant by Ministry of Agriculture Malaysia (304/CIPPM/650736/k123). Chern. E. Oon was supported by the RUI Universiti Sains Malaysia Grant (1001/CIPPM/812156)

Establishment of in vitro and in vivo anti-colon cancer efficacy of essential oils containing oleo-gum resin extract of Mesua ferrea

Proven the great potential of essential oils as anticancer agents, the current study intended to explore molecular mechanisms responsible for in vitro and in vivo anti-colon cancer efficacy of essential oil containing oleo-gum resin extract (RH) of Mesua ferrea. MTT cell viability studies showed that RH had broad spectrum cytotoxic activities. However, it induced more profound growth inhibitory effects towards two human colon cancer cell lines i.e., HCT 116 and LIM1215 with an IC50 values of 17.38 ± 0.92 and 18.86 ± 0.80 μg/mL respectively. RH induced relatively less toxicity in normal human colon fibroblasts i.e., CCD-18co. Cell death studies conducted, revealed that RH induced characteristic morphological and biochemical changes in HCT 116. At protein level it down-regulated expression of multiple pro-survival proteins i.e., survivin, xIAP, HSP27, HSP60 and HSP70 and up-regulated expression of ROS, caspase-3/7 and TRAIL-R2 in HCT 116. Furthermore, significant reduction in invasion, migration and colony formation potential was observed in HCT 116 treated with RH. Chemical characterization by GC–MS and HPLC methods revealed isoledene and elemene as one the major compounds. RH showed potent antitumor activity in xenograft model. Overall, these findings suggest that RH holds a promise to be further studied for cheap anti-colon cancer naturaceutical development.The authors would like to acknowledge the Institute of Postgraduate Studies at Universiti Sains Malaysia for providing a USM Fellowship (PFD0009/12(R)). We would also like to acknowledge USM for providing funding through a University Grant (RUT 1001/PFARMASI/851001)

Molecular mechanisms responsible for programmed cell death-inducing attributes of terpenes from Mesua ferrea stem bark towards human colorectal carcinoma HCT 116 cells

The current study explored the in vitro anticancer properties of Mesua ferrea stem bark (SB) extract towards human colon carcinoma HCT116 cells. SB was successively extracted with different solvents using soxhlet apparatus. MTT assay was employed to test toxicity against different cancer and normal cell lines. Active extract (n-Hexane) was fractionated by column chromatography (CC) to get the most active fraction (F-3). Series of in vitro assays were employed to characterize cytotoxic nature of F-3. Antioxidant properties of F-3 were assessed using DPPH, ABTS and FRAP assays followed by GC-MS analysis. Intracellular ROS levels were measured by DCFH-DA fluorescent assay. Finally, cell signalling pathways and their downstream proteins targeted by F-3 were studied using 10-cancer pathway and human apoptosis protein profilers and in silico docking studies. n-Hexane extract and its fraction (F-3) showed potent anti-proliferative effect against HCT 116. Programmed cell death (PCD) studies showed that F-3 modulated the expression of multiple proteins in HCT 116. F-3 showed weak antioxidant activity in all the models, while significant increase in ROS was observed in HCT 116. GC-MS analysis revealed that F-3 was majorly comprised of terpenes. Data of pathway profiler and in silico studies revealed that F-3 downregulated the expression of NF-kB and HIF-1 alpha pathways. Overall these results demonstrate that anticancer effects of M. ferrea stem bark towards human colon carcinoma are mainly due to its terpenes contents