A Priori Activation of Apoptosis Pathways of Tumor (AAAPT) technology: Development of targeted apoptosis initiators for cancer treatment
Authors: Ramasamy Paulmurugan
Marco Tomasetti
Cynthia Ma
Harikrishna Nakshatri
Sekar T Verapazham
Sandeep Rajput
Raghu S Pandurangi
Manjushree Anjanappa
Journal: PLoS ONE (2021)
Discipline: Multidisciplinary
Keywords: Cancer cells; desensitization; survival pathways; cell death pathways; therapeutic dose
Affiliations: Sci-Engi-Medco Solutions Inc., St Charles, Missouri, United States of America., Department of Clinical and Molecular Sciences, Section of Experimental and Occupational Medicine, Polytechnic University of Marche, Ancona, Italy., Molecular Imaging Program at Stanford (MIPS), Canary Center for Cancer Early Detection, Department of Radiology, Stanford University School of Medicine, Palo Alto, California, United States of America., Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, United States of America., Department Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.

Abstract:  Cancer cells develop tactics to circumvent the interventions by desensitizing themselves to interventions. Amongst many, the principle routes of desensitization include a) activation of survival pathways (e.g. NF-kB, PARP) and b) downregulation of cell death pathways (e.g. CD95/CD95L). As a result, it requires high therapeutic dose to achieve tumor regression which, in turn damages normal cells through the collateral effects. Methods are needed to sensitize the low and non-responsive resistant tumor cells including cancer stem cells (CSCs) in order to evoke a better response from the current treatments. Current treatments including chemotherapy can induce cell death only in bulk cancer cells sparing CSCs and cancer resistant cells (CRCs) which are shown to be responsible for high recurrence of disease and low patient survival. Here, we report several novel tumor targeted sensitizers derived from the natural Vitamin E analogue (AMP-001-003). The drug design is based on a novel concept "A priori activation of apoptosis pathways of tumor technology (AAAPT) which is designed to activate specific cell death pathways and inhibit survival pathways simultaneously and selectively in cancer cells sparing normal cells. Our results indicate that AMP-001-003 sensitize various types of cancer cells including MDA-MB-231 (triple negative breast cancer), PC3 (prostate cancer) and A543 (lung cancer) cells resulting in reducing the IC-50 of doxorubicin in vitro when used as a combination. At higher doses, AMP-001 acts as an anti-tumor agent on its own. The synergy between AMP-001 and doxorubicin could pave a new pathway to use AAAPT leading molecules as neoadjuvant to chemotherapy to achieve better efficacy and reduced off-target toxicity compared to the current treatments. 

Retracted: No

PubPeer comments:
 Figure 6 appears to have a repeated image. ***  , 
 Yes, this does look like a repeated image and added inadvertently. Our apologies. We have more images and we will send a correction. Appreciate your diligent look at our paper and will send correction shortly. , 
 I have been trying to upload the correct file but it is not letting me upload it. We will send corrected figure to the journal. My apologies for the inconvenience. Hari , 
  , 
 In Figure 8, image duplication for GAPDH immunoblots of two different groups. , 
 These experiments have nothing to do with my lab. These were done by the corresponding author or his other collaborators. Hopefully, he will respond and provide details of who did the experiment and, particularly, who assembled the figures , 
 #6 The authors may wish to contact the journal about the supplemental files as well. According to the paper, all data is included in the paper and supplemental files, however the purported original gels for Figure 8A do not seem to resemble the published figure. *** Original  *** Published figure  , 
 Another odd thing about the supplemental files. Figure 5C and the  original data for Figure 5C do not seem to match. In addition the first two lanes of the actin band in the  original data for Figure 5C are crudely spliced on. Maybe I ve got the wrong file somehow. This is an NIH funded study. ***  , 
 Thanks for the keen eyes, we will contact Journal and rectify some of them. Some of them are labeling issue. I am the corresponding Author. Please send the comments to me only. Thanks ,