Repurposing Established Compounds to Target Pancreatic Cancer Stem Cells (CSCs)

Abstract

The diagnosis of pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis, in particular, when patients present with unresectable disease. While significant progress has been made in understanding the biology of PDAC, this knowledge has not translated into a clear clinical benefit and current chemotherapeutic strategies only offer a modest improvement in overall survival. Accordingly, novel approaches are desperately needed. One hypothesis that could—at least in part—explain the desolate response of PDAC to chemotherapy is the so-called cancer stem cell (CSC) concept, which attributes specific traits, such as chemoresistance, metastatic potential and a distinct metabolism to a small cellular subpopulation of the whole tumor. At the same time, however, some of these attributes could make CSCs more permissive for novel therapeutic strategies with compounds that are already in clinical use. Most recently, several publications have tried to enlighten the field with the idea of repurposing established drugs for antineoplastic use. As such, recycling drugs could present an intriguing and fast-track method with new therapeutic paradigms in anti-cancer and anti-CSC treatments. Here, we aim to summarize important aspects and novel findings of this emerging field.

The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer

“…Natural and synthetic molecules, as well as Food and Drug Administration (FDA)-approved drugs candidate for repurposing in oncology are currently being considered as single compounds, or in combination for PC therapy [3][4][5][6][7][8]. Repurposing of approved non-anticancer drugs in cancer therapy may have several advantages, including good safety profiles and recognized pharmacokinetic properties in term of absorption, metabolism and toxicity, which may accelerate the clinical translation in cancer therapy of preclinical results obtained with these drugs [9][10][11].…”

Co‐targeting of lysosome and mitophagy in cancer stem cells with chloroquine analogues and antibiotics

“…[90][91][92] Based on in vitro substitute CSC assays, numerous classes of FDA-approved antibiotics including erythromycins (azithromycin), glycylcycline (tigecycline), tetracyclines (doxycycline), fluoroquinolones (levofloxacin and ciprofloxacin) and atovaquone (chloroquine analogues) have been found to markedly reduce tumorsphere development in several cancer cells including breast, lung, prostate and PDAC. 92,93 For instance, tigecycline selectively kills CSCs of acute myeloid leukaemia (AML) by suppression of mitochondrial translation. 94 Azithromycin in combination with chemotherapy (paclitaxel and cisplatin) shows a positive response of one-year survival of stage III/IV non-small cell lung cancer (NSCLC) patients.…”

Targeting cancer stem cells with dietary phytochemical - Repositioned drug combinations

“…Similarly, the list of CSC-targeting existing drugs is expanding. Other repurposed drugs include anti-allergy drug tranilast, cholesterollowering statins (simvastatin and lovastatin), and anti-alcoholism drug disulfiram [6,19,25,128,129]. We anticipate more to come.…”