A Priori Activation of Apoptosis Pathways of Tumor (AAAPT) technology: Development of targeted apoptosis initiators for cancer treatment.

Raghu S Pandurangi,Cynthia Ma,Harikrishna Nakshatri,Sandeep Rajput,Ramasamy Paulmurugan,Manjushree Anjanappa,Marco Tomasetti,Sekar T Verapazham

doi:10.1371/journal.pone.0225869

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.

Highlights

Tumor cells have a remarkable ability to circumvent endogenous and exogenous toxicities by deactivating cell death pathways and thereby desensitizing themselves to interventions [1]
New advances in the molecular biology of cancer cells reveal that cancer stem cells (CSCs) and cancer resistant cells (CRCs) escape cell death by activating the survival pathway (e.g. NF-kB) and by hyperactivating DNA repair enzyme Poly ADP ribose polymerase (PARP) which repairs DNA breaks caused by oncology drugs
We have developed a novel technology, “A priori Activation of Apoptosis Pathways of Tumor” (AAAPT) as a strategy to sensitize low responsive tumor cells in order to evoke a better response from chemotherapy [12]

Summary

Introduction

Tumor cells have a remarkable ability to circumvent endogenous and exogenous toxicities by deactivating cell death pathways and thereby desensitizing themselves to interventions [1]. Defects in apoptosis pathways (e.g. CD95, APO-1/Fas) would make tumor cells insensitive to chemotherapy [2]. Restoration of the apoptotic machinery with apoptosis inducing ligands (apoptogens) is an area of active investigation in the drug development. Several agents have been developed to activate TRAIL [5], to downregulate Bcl-2 [6] and to restore the function of the mutated p53 in order to sensitize tumor cells. New advances in the molecular biology of cancer cells reveal that cancer stem cells (CSCs) and cancer resistant cells (CRCs) escape cell death by activating the survival pathway (e.g. NF-kB) and by hyperactivating DNA repair enzyme Poly ADP ribose polymerase (PARP) which repairs DNA breaks caused by oncology drugs. For CSCs and CRCs may have to consider offsetting these dysregulated pathways. Tumor sensitizers, potentially can be used as neoadjuvant to chemotherapy to expand the therapeutic index of chemotherapy [7]

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