“Hippocrates, the father of natural medicine, coined the phrase “let food be your medicine and your medicine be your food”.”

Papers of Interest

Modulation of macrophage polarization and lung cancer cell stemness by MUC1 and development of a related small-molecule inhibitor pterostilbene 

Wen-Chien Huang1,2,4, Mei-Lin Chan1,2,4, Ming-Jen Chen4,5, Tung-Hu Tsai1,6 and Yu-Jen Chen1,3,4,7 

1 MacKay Medical College, Taipei, Taiwan
2 Department of Surgery, Division of Thoracic Surgery, MacKay Memorial Hospital, Taipei, Taiwan
3 Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan
4 Institute of Traditional Medicine, School of Medicine, National Yang Ming University, Taipei, Taiwan
5 Department of Surgery, Division of Colorectal Surgery, MacKay Memorial Hospital, Taipei, Taiwan
6 Department of Education and Research, Taipei City Hospital, Taipei, Taiwan
7 College of Chinese Medicine, China Medical University, Taichung, Taiwan
Correspondence to: Yu-Jen Chen, email: chenmdphd@gmail.com
Correspondence to: Tung-Hu Tsai, email: thtsai@ym.edu.tw 

Keywords: tumor-associated macrophages (TAMs), lung cancer stem cells (CSCs), MUC1, pterostilbene, M2 polarization, Immunology and Microbiology Section, Immune response, Immunity
Received: July 31, 2015 Accepted: May 17, 2016 Published: June 04, 2016 

ABSTRACT

Tumor-associated macrophages (TAMs) polarized to the M2 phenotype play key roles in tumor progression in different cancer types, including lung cancer. MUC1 expression in various types of cancer is an indicator of poorer prognosis. Elevated MUC1 expression has been reported in inflammatory lung macrophages and is associated with lung cancer development. Here, we investigated the role of M2-polarized TAMs (M2-TAMs) in the generation of lung cancer stem cells (LCSCs) and tested pterostilbene, a small-molecule agent that modulates MUC1 expression in lung cancer cells, with the goal of subverting the microenvironment toward a favorable anti-tumor impact. We found that MUC1 was overexpressed in lung cancer patients, which was associated with poor survival rates. M2-TAMs and cancer cell lines were co-cultured in an experimental tumor microenvironment model. The expression levels of MUC1 and cancer stemness genes significantly increased in lung cancer cells in the presence of the M2-TAM cells. Intriguingly, pterostilbene dose-dependently suppressed self-renewal ability in M2-TAMs-co-cultured lung cancer cells, and this suppression was accompanied by downregulation of MUC1, NF-κB, CD133, β-catenin, and Sox2 expression. Moreover, MUC1-silenced M2-TAMs exhibited a significantly lower ability to promote LCSC generation and decreased levels of NF-κB, CD133, and Sox2. The results suggest that MUC1 plays an important role in TAM-induced LCSC progression. Pterostilbene may have therapeutic potential for modulating the unfavorable effects of TAMs in lung cancer progression.


Case-specific potentiation of glioblastoma drugs by pterostilbene 

Linnéa Schmidt1, Sathishkumar Baskaran1, Patrik Johansson1, Narendra Padhan1, Damian Matuszewski2, Lydia C Green3, Ludmila Elfineh1, Shimei Wee4, Maria Häggblad5, Ulf Martens5, Bengt Westermark1, Karin Forsberg-Nilsson1, Lene Uhrbom1, Lena Claesson-Welsh1, Michael Andäng4, Ida-Maria Sintorn2, Bo Lundgren5, Ingrid Lönnstedt1, Cecilia Krona1, Sven Nelander

1Life Laboratory, Uppsala University, Uppsala Sweden
2Centre for Image Analysis, Department of Information Technology, Uppsala University, Uppsala, Sweden
3Sahlgrenska Cancer Center, Institute of Medicine, Gothenburg, Sweden
4Department of Physiology and Pharmacology, Karolinska Institute, Sweden
5Cell Screening Facility, Science for Life Laboratory Stockholm, Department of Biochemistry and Biophysics, Stockholm University, Solna, Sweden

Correspondence to: Sven Nelander, email: sven.nelander@igp.uu.se
Keywords: glioblastoma, glioblastoma initiating cells, stilbenoids, drug repurposing, cancer therapeutics
Received: March 12, 2016 Accepted: September 16, 2016 Published: September 28, 2016 

ABSTRACT

Glioblastoma multiforme (GBM, astrocytoma grade IV) is the most common malignant primary brain tumor in adults. Addressing the shortage of effective treatment options for this cancer, we explored repurposing of existing drugs into combinations with potent activity against GBM cells. We report that the phytoalexin pterostilbene is a potentiator of two drugs with previously reported anti-GBM activity, the EGFR inhibitor gefitinib and the antidepressant sertraline. Combinations of either of these two compounds with pterostilbene suppress cell growth, viability, sphere formation and inhibit migration in tumor GBM cell (GC) cultures. The potentiating effect of pterostilbene was observed to a varying degree across a panel of 41 patient-derived GCs, and correlated in a case specific manner with the presence of missense mutation of EGFR and PIK3CA and a focal deletion of the chromosomal region 1p32. We identify pterostilbene-induced cell cycle arrest, synergistic inhibition of MAPK activity and induction of Thioredoxin interacting protein (TXNIP) as possible mechanisms behind pterostilbene’s effect. Our results highlight a nontoxic stilbenoid compound as a modulator of anticancer drug response, and indicate that pterostilbene might be used to modulate two anticancer compounds in well-defined sets of GBM patients.