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. 2017 Nov 1;8(61):104347-104358.
doi: 10.18632/oncotarget.22238. eCollection 2017 Nov 28.

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

April B Cabang  1 , Keya De Mukhopadhyay  1 , Sarah Meyers  2 , Jay Morris  1 , Paul V Zimba  3 , Michael J Wargovich  1
Affiliations

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

April B Cabang et al. Oncotarget. .

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.

Keywords: autophagy; colon cancer; euglenophycin; ichthyotoxin; therapy.

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Conflict of interest statement

CONFLICTS OF INTEREST The authors have no potential conflicts of interest.

Figures

Figure 1
Figure 1. Chemical structures of euglenophycin and solenopsin A
Figure 2
Figure 2. Euglenophycin inhibits proliferation and clonogenicity of HCT116, HT29, and SW620 colon cancer cell lines
(A-C) MTT cytotoxicity assay; (D-F) quantified cell cycle analysis by propidium iodide staining and flow cytometry (representative images are in Supplementary Figure 1) after 48 hr toxin treatment; (G-L) colony formation assay visualized by crystal violet with quantified values and representative images: (G) and (H), HCT116; (I) and (J), HT29; (K) and (L), SW620. Values indicate mean ± SE (from three independent experiments). Eug is euglenophycin; Baf is Bafilomycin A; Veh is vehicle control (0 μM). (A-C) *p<0.05, **p<0.01 at 48 hr and ɸɸp<0.01, ɸɸɸp<0 at 72 hr. (D-H) * p<0.05, **p<0.01, *** p<0.001.
Figure 3
Figure 3. Autophagic modulatory effects of euglenophycin are cell type-dependent
Alterations in autophagic flux (detected by CYTO-ID and flow cytometry) induced by treatment with euglenophycin or control drugs (autophagy activator Rapamycin or Rapa; inhibitor Chloroquine or Chlq) in (A) and (B), HCT116; (C) and (D), HT29; and (E) and (F), SW620 cancer cells. Values indicate mean ± SE; * p<0.05, ** p<0.01, *** p<0.001.
Figure 4
Figure 4. Suppression of migratory potential by euglenophycin (EUG) is cell type-dependent
Wound healing measured by two parameters, wound width and wound confluence. Scratch assay quantification with (A) and (B), HCT 116; (C) and (D), HT 29. Representative images are in Supplementary Figure 3. *p ≤ 0.05 EUG 0 μM vs 16.4 μM; ɸp ≤ 0.05 EUG 0 μM vs 114.6 μM; ɸɸp ≤ 0.01 EUG 0 μM vs 114.6 μM; ɸɸɸ p ≤ 0.001 EUG 0 μM vs 114.6 μM; values indicate mean ± SE; n=8 per treatment group.
Figure 5
Figure 5. Euglenophycin inhibits in vivo tumor growth of colon cancer cells similarly as CPT-11 (standard chemotherapeutic) in mouse xenograft models
Tumor volumes (n=10 per cell line) of mice injected with (A) HCT116 and (B) HT29 cells, respectively. *p ≤ 0.05 control vs toxin (EUG); **p ≤ 0.001 control vs toxin; ɸp ≤ 0.001 control vs CPT-11; values indicate ± SD. Intraperitoneal administration of CPT-11 or euglenophycin were done daily from day 10 to day 15 post-implantation.
Figure 6
Figure 6. Euglenophycin (EUG) modulated protein expression of autophagy markers in HCT116 and HT29 xenografts
Representative western blot is presented in (A) and quantification is shown in (B-G). * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001; values indicate mean ± SE (analyzed 3 tumors per group for each cell type).
See this image and copyright information in PMC

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