A novel synthetic C-1 analogue of 7-deoxypancratistatin induces apoptosis in p53 positive and negative human colorectal cancer cells by targeting the mitochondria: enhancement of activity by tamoxifen
Authors: James McNulty
Kevinjeet Mahngar
Pardis Akbari-Asl
Jonathan Collins
Phillip Tremblay
Dennis Ma
Tomas Hudlicky
Siyaram Pandey
Journal: Investigational New Drugs (2012)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: pancratistatin; apoptosis; colorectal cancer; synthetic analogues; mitochondria
Affiliations: Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, ON, N9B 3P4, Canada.

Abstract:  The natural compound pancratistatin (PST), isolated from the Hymenocallis littoralis plant, specifically induces apoptosis in many cancer cell lines. Unlike many other chemotherapeutics, PST is not genotoxic and has minimal adverse effects on non-cancerous cells. However, its availability for preclinical and clinical work is limited due to its low availability in its natural source and difficulties in its chemical synthesis. Several synthetic analogues of 7-deoxypancratistatin with different modifications at C-1 were synthesized and screened for apoptosis inducing activity in human colorectal cancer (CRC) cells. We found that a C-1 acetoxymethyl derivative of 7-deoxypancratistatin, JC-TH-acetate-4 (JCTH-4), was effective in inducing apoptosis in both p53 positive (HCT 116) and p53 negative (HT-29) human CRC cell lines, demonstrating similar efficacy to that of natural PST. JCTH-4 was able to decrease mitochondrial membrane potential (MMP), increase levels of reactive oxygen species in isolated mitochondria, cause release of the apoptogenic factor cytochrome c (Cyto c) from isolated mitochondria, and induce autophagy in HCT 116 and HT-29 cells. Interestingly, when JCTH-4 was administered with tamoxifen (TAM), there was an enhanced effect in apoptosis induction, reactive oxygen species (ROS) production and Cyto c release by isolated mitochondria, and autophagic induction by CRC cells. Minimal toxicity was exhibited by a normal human fetal fibroblast (NFF) and a normal colon fibroblast (CCD-18Co) cell line. Hence, JCTH-4 is a novel compound capable of selectively inducing apoptosis and autophagy in CRC cells alone and in combination with TAM and may serve as a safer and more effective alternative to current cancer therapies. 

Retracted: No

PubPeer comments:
 Figure 3C. Much more similar than you would expect. https: imgur.com LIdEB7F , 
 2020 erratum. https: www.atsjournals.org doi full 10.1165 rcmb.v63erratum1 The authors wish to correct errors in the two right panels of Figure 3C in their article published in the December 2009 issue of AJRCMB (1). To prepare the original two panels, lanes from the scan of the gel were spliced so that the control lane could be adjacent to the two u03b1,u03b2-meATP and BzATP-stimulated lanes (the annotated scan of the original gel is shown below). In the revised version of the panels below, a white space has been inserted to separate the control lanes from the u03b1,u03b2-meATP and BzATP lanes, indicating noncontiguous lanes. They also made an error during construction of the original figure in that the same total IKK-u03b1 bands were used in the two panels. This error has been corrected in the revised version of the two panels of Figure 3C, which now uses the appropriate IKK-u03b1 lanes. ,