Toosendanin Inhibits Colorectal Cancer Cell Growth Through the Hedgehog Pathway by Targeting SHH

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide. It is complex and often fatal and is associated with a high disease-related mortality. The Hedgehog (Hh) signalling pathway plays indispensable roles in CRC. Many studies have proven that Shh is overexpressed in cancer stem cells (CSCs) and shown that SHH overexpression is positively correlated with CRC tumorigenesis. The development of new drugs to kill CRC cells through the Hh pathway is urgently needed. Toosendanin (TSN), a natural triterpenoid saponin extracted from the bark or fruit of Melia toosendan Sieb. et Zucc., has been proven to inhibit various tumours. Here, we demonstrated that TSN inhibited the CRC cell growth through the Hh signalling pathway by targeting SHH. TSN has promising potential as an antitumour agent for CRC treatment.

Two new polymorphic forms of combretastatin A-4, an antitumour agent

Two new polymorphic forms of combretastatin A-4 {systematic name: 2-methoxy-5-[(E)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol, C18H20O5, CA-4}, an inhibitor of tubulin polymerization at the colchicine binding site, were identified. A number of crystallization attempts led to the orthorhombic form, with two molecules in the asymmetric part of the unit cell; obtaining a different form required the experiment to be moved to another laboratory. None of the attempts resulted in the monoclinic form described earlier. The three different forms contain molecules of significantly different geometries, which can be related to conformational freedom, postulated as the result of biological studies. In addition, the packing modes in all three forms are basically different. The structural differences at both the molecular and the supramolecular level have also been studied via calculations of energies and a topological analysis of the electron density. The results confirm the role of weak interactions in the determination of crystal architecture and additionally hint at an explanation for the results of crystallization attempts: the new monoclinic form has significantly lower energy than the form reported earlier.

Novel (−)-goniofufurone mimics: Synthesis, antiproliferative activity and SAR analysis

Divergent syntheses of novel (?)-goniofufurone mimics with an alkoxymethyl group as the side chain have been accomplished from D-glucose in nine synthetic steps and in overall yields 6.7?8.7 %. Their in vitro antiproliferative activity was evaluated against eight human tumour cell lines as well as a single normal cell line. All analogues demonstrated powerful to good antiproliferative effects toward all malignant cell lines under evaluation. Against the HL-60 cell line, all mimics showed increased activities being 27- to 1604-fold more potent than the lead compound, (?)-goniofufurone. Remarkably, the majority of synthesized analogues displayed higher or similar activity to the commercial antitumour agent doxorubicin (DOX) against A549 cell line. The most potent compound exhibited 196-fold stronger cytotoxicity than DOX in the culture of this cell line.

Antitumour and Acute Toxicity Studies of 4-(pyridin-4-yl)-6-(thiophen-2-yl)pyrimidin-2(1H)-one Against Ehrlich Ascites Carcinoma and Sarcoma-180

In an effort to discover an effective and selective antitumour agent, synthesis and anti-cancer potential of 4-(pyridin-4-yl)-6-(thiophen-2-yl)pyrimidin-2(1H)-one (SK-25), which has been reported earlier by us with significant cytotoxicity towards MiaPaCa-2 malignant cells, with an IC50 value of 1.95 μM and was found to instigate apoptosis. In the present study, the antitumour efficacy of SK-25 was investigated on Ehrlich ascites tumour (solid), Sarcoma 180 (solid) tumour and Ehrlich ascites carcinoma. The compound was found to inhibit tumour development by 94.71% in Ehrlich ascites carcinoma (EAC), 59.06% in Ehrlich tumour (ET, solid) and 45.68% in Sarcoma-180 (solid) at 30 mg/kg dose. Additionally, SK-25 was established to be non-toxic at a maximum tolerated dose of 1000 mg/kg in acute oral toxicity in Swiss-albino mice. Computer-based predictions also show that the compounds could have an interesting DMPK profile. The current study provides insight for further investigation of the antitumour potential of the molecule.

Tetramethylpyrazine blocks TFAM degradation and up-regulates mitochondrial DNA copy number by interacting with TFAM

The natural small molecule compound: 2,3,5,6-tetramethylpyrazine (TMP), is a major component of the Chinese medicine Chuanxiong, which has wide clinical applications in dilating blood vessels, inhibiting platelet aggregation and treating thrombosis. Recent work suggests that TMP is also an antitumour agent. Despite its chemotherapeutic potential, the mechanism(s) underlying TMP action are unknown. Herein, we demonstrate that TMP binds to mitochondrial transcription factor A (TFAM) and blocks its degradation by the mitochondrial Lon protease. TFAM is a key regulator of mtDNA replication, transcription and transmission. Our previous work showed that when TFAM is not bound to DNA, it is rapidly degraded by the ATP-dependent Lon protease, which is essential for mitochondrial proteostasis. In cultured cells, TMP specifically blocks Lon-mediated degradation of TFAM, leading to TFAM accumulation and subsequent up-regulation of mtDNA content in cells with substantially low levels of mtDNA. In vitro protease assays show that TMP does not directly inhibit mitochondrial Lon, rather interacts with TFAM and blocks degradation. Pull-down assays show that biotinylated TMP interacts with TFAM. These findings suggest a novel mechanism whereby TMP stabilizes TFAM and confers resistance to Lon-mediated degradation, thereby promoting mtDNA up-regulation in cells with low mtDNA content.