Combination curcumin and (−)-epigallocatechin-3-gallate inhibits colorectal carcinoma microenvironment-induced angiogenesis by JAK/STAT3/IL-8 pathway

Abstract

Tumor microenvironment has a crucial role in cancer development and progression, whereas the mechanism of how it regulates angiogenesis is unclear. In this study, we simulated the colorectal carcinoma microenvironment by conditioned medium (CM) of colorectal carcinoma cell lines (SW620, HT-29, HCT116) supernatant or colorectal carcinoma tissue homogenate supernatant to induce normal endothelial cells (NECs). We found that colorectal carcinoma CM promoted tumor angiogenesis by coercing NECs toward tumor endothelial cells (TECs) with the activation of the JAK/STAT3 signaling pathway. Antibody array analysis showed HT-29 supernatant contained numerous angiogenesis-related proteins, especially IL-8. Interestingly, the production of IL-8 in NECs induced by HT-29 CM was also increased. We also verified the crucial role of IL-8 in promoting the CM-induced angiogenesis, as IL-8 repression by neutralizing antibody abolished the transition of NECs toward TECs. Curcumin and (−)-epigallocatechin-3-gallate (EGCG) are broadly investigated in cancer chemoprevention. However, poor bioavailability hurdles their application alone, and the mechanism of their anti-angiogenesis still need to be illuminated. Here, we found that curcumin combination with EGCG attenuated the tumor CM-induced transition of NECs toward TECs by inhibiting JAK/STAT3 signaling pathway. Furthermore, the combination of curcumin and EGCG markedly reduced tumor growth and angiogenesis in the colorectal carcinoma PDX mouse model, and the combined anti-angiogenic effect was better than that of curcumin or EGCG alone. Taken together, our findings provide a new mechanism of tumor angiogenesis, and the combination of curcumin and EGCG represents a potential anti-angiogenic therapeutic method for colorectal carcinoma.

Inhibition of skin tumor promotion by TPA using a combination of topically applied ursolic acid and curcumin

“…15 Another previous study in our laboratory, mentioned above, showed the combination of UA + Res inhibited skin tumor promotion by TPA to a greater extent than either compound alone. 7 Jin et al 46 showed the combination of Curc and epigallocatechin-3-gallate (EGCG) suppressed colorectal carcinoma PDX tumor growth to a greater extent than either compound alone. Another study demonstrated the combination of luteolin and EGCG inhibited xenograft tumor growth of a head and neck squamous cell carcinoma cell line to a greater extent than either compound alone.…”

EGCG Mediated Targeting of Deregulated Signaling Pathways and Non-Coding RNAs in Different Cancers: Focus on JAK/STAT, Wnt/β-Catenin, TGF/SMAD, NOTCH, SHH/GLI, and TRAIL Mediated Signaling Pathways

“…EGCG potently inhibited BCR/ABL oncoprotein and the JAK2/STAT3/AKT pathway in BCR/ABL+ CML cell lines [7]. Curcumin worked synchronously with EGCG and considerably interfered with tumor conditioned media-induced transition of normal endothelial cells toward tumor endothelial cells by inhibition of the JAK/STAT3 signaling pathway [8].…”

Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science

“…Curcumin in combination with (−)-epigallocatechin-3-gallate markedly reduces tumor growth and microenvironmentinduced angiogenesis via modulation of the JAK/STAT3/ IL-8 pathway in colorectal carcinoma. 32 Treatment with resveratrol can downregulate angiogenesis via decreased expression of VEGF in the tumor microenvironment. 54 Berberine has been shown to reduce tumor-induced angiogenesis both in vitro and in vivo.…”