Therapeutic effects of the euglenoid ichthyotoxin, euglenophycin, in colon cancer.

April B Cabang,Jay Morris,Keya De Mukhopadhyay,Paul V Zimba,Michael J Wargovich,Sarah Meyers

doi:10.18632/oncotarget.22238

Abstract

Colorectal cancer (CRC) remains one of the most commonly diagnosed cancers and the 3rd leading cause of cancer-related mortality. The emergence of drug resistance poses a major challenge in CRC care or treatment. This can be addressed by determining cancer mechanisms, discovery of druggable targets, and development of new drugs. In search for novel agents, aquatic microorganisms offer a vastly untapped pharmacological source that can be developed for cancer therapeutics. In this study, we characterized the anti-colorectal cancer potential of euglenophycin, a microalgal toxin from Euglena sanguinea. The toxin (49.1-114.6 μM) demonstrated cytotoxic, anti-proliferative, anti-clonogenic, and anti-migration effects against HCT116, HT29, and SW620 CRC cells. We identified G1 cell cycle arrest and cell type - dependent modulation of autophagy as mechanisms of growth inhibition. We validated euglenophycin’s anti-tumorigenic activity in vivo using CRL:Nu(NCr)Foxn1nu athymic nude mouse CRC xenograft models. Intraperitoneal toxin administration (100 mg/kg; 5 days) decreased HCT116 and HT29 xenograft tumor volumes (n=10 each). Tumor inhibition was associated with reduced expression of autophagy negative regulator mechanistic target of rapamycin (mTOR) and decreased trend of serum pro-inflammatory cytokines. Together, these results provide compelling evidence that euglenophycin can be a promising anti-colorectal cancer agent targeting multiple cancer-promoting processes. Furthermore, this study supports expanding natural products drug discovery to freshwater niches as prospective sources of anti-cancer compounds.

Highlights

Colorectal cancer (CRC) remains the 3rd leading cause of cancer-related deaths [1]
Freshwater algae are better studied than marine algae, drug discovery efforts have been focused on marine species
Toxin treatment resulted in significant G1-phase cell cycle arrest (Figure 2D-2F; Supplementary Figure 1) in HCT116 and HT29 cells at 49.1-114.6 μM, compared to minimal effect on SW620 cells

Summary

Introduction

Colorectal cancer (CRC) remains the 3rd leading cause of cancer-related deaths [1]. Euglenophycin has demonstrable cytotoxic activity against human colon and neuroblastoma cancer cell lines [13, 20, 21] that prompted us to investigate mechanisms of action in CRC cells (HCT116, HT29, and SW620) and in mouse xenograft models. The toxin exhibits anti-migratory effects in human CRC cells and suppresses tumor growth and pro-inflammatory markers in HCT116 and HT29 xenograft models.

Results

Conclusion