Enhancing Chemosensitivity of Breast Cancer Stem Cells by Downregulating SOX2 and ABCG2 Using Wedelolactone-encapsulated Nanoparticles
Authors: Zarqua Jamal
Sreemanti Das
Urmi Chatterji
Ranodeep Chatterjee
Pritha Mukherjee
Journal: Molecular Cancer Therapeutics (2019)
Discipline: CLINICAL MEDICINE
Keywords: breast cancer; cancer stem cells; wedelolactone; PLGA nanoparticles; drug resistance
Affiliations: Cancer Research Laboratory, Department of Zoology, University of Calcutta, Kolkata, India., Cancer Research Laboratory, Department of Zoology, University of Calcutta, Kolkata, India. .

Abstract:  A major caveat in the treatment of breast cancer is disease recurrence after therapeutic regime at both local and distal sites. Tumor relapse is attributed to the persistence of chemoresistant cancer stem cells (CSC), which need to be obliterated along with conventional chemotherapy. Wedelolactone, a naturally occurring coumestan, demonstrates anticancer effects in different cancer cells, although with several limitations, and is mostly ineffective against CSCs. To enhance its biological activity in cancer cells and additionally target the CSCs, wedelolactone-encapsulated PLGA nanoparticles (nWdl) were formulated. Initial results indicated that nanoformulation of wedelolactone not only increased its uptake in breast cancer cells and the CSC population, it enhanced drug retention and sustained release within the cells. Enhanced drug retention was achieved by downregulation of SOX2 and ABCG2, both of which contribute to drug resistance of the CSCs. In addition, nWdl prevented epithelial-to-mesenchymal transition, suppressed cell migration and invasion, and reduced the percentage of breast cancer stem cells (BCSC) in MDA-MB-231 cells. When administered in combination with paclitaxel, which is known to be ineffective against BCSCs, nWdl sensitized the cells to the effects of paclitaxel and reduced the percentage of ALDH+ BCSCs and mammospheres. Furthermore, nWdl suppressed growth of solid tumors in mice and also reduced CD44+/CD24-/low population. Taken together, our data imply that nWdl decreased metastatic potential of BCSCs, enhanced chemosensitivity through coordinated regulation of pluripotent and efflux genes, and thereby provides an insight into effective drug delivery specifically for obliterating BCSCs. 

Retracted: No

PubPeer comments:
 All the western blot data in figure 3C are exact same as the western blot data in figure 6E. Note: these are completely different experiments. [For clear identification, same blots are indicated with same colored boxes.] Please note although the blots are same, but has been used as the expression result of different proteins. Also to note: even the blots are same, the densitometric analysis are showing different values to create difference .  , 
 Serious concern with another data presented in Figure 4D. Same areas marked with same colors. Zoom the image to verify. Although it s very clear.  , 
 #2 You have missed one area. I have marked with pink arrow (the area inside pink circle).  Zoomed in for clear identification. See how this has been done.  , 
 Unusual square shape area in cultured cell images presented in figure 4F (inside the circles).  ,