Development of a New Combination Compound (Cyclopamine) Isolated from Veratrum californicum and 5-FU Acting as Anti-invasive and Initiator of Intrinsic Apoptosis Mechanism against Aggressive Type Colorectal Cancer Cells

Abstract

Characteristics of programmed cell death are generally regarded as defined by cell outgrowth or cellular aging and distinct morphological characteristics featuring nuclear condensation and formation of apoptotic bodies. Apoptosis is considered to have a function at cellular level and is essential to long-lived cell differentiation undergoing senescence and apoptosis. Inappropriate apoptosis is a factor that results in serious conditions, causing multiple disease progression as well as cancer. The ability to modulate the life or death of a cancer cell is recognized for its immense therapeutic potential. Therefore, the research findings that are focused on the elucidation of a newly synthesized drug or drug derived from a natural plant to stop the cell cycle mechanism and signaling pathways that control cell cycle arrest and apoptosis are considered necessary. The field research of apoptosis is moving forward at a rapid rate. The goal of this paper is to investigate a natural active constituent, which is simply identified as “a drug for near future co-chemotherapy”, as well as to explore the ability to activate the apoptotic pathway. Our results demonstrated that cyclopamine provides an excellent anti-tumor activity and changing of the morphology of cancerous cells in the early and late phases of apoptosis, indicating that cyclopamine has the potential to chemosensitize SW-620 cancer cells to 5-FU based chemotherapy, which may be useful for the treatment of colorectal cancer and the fight to overcome drug resistance in advanced colorectal cancer.

bFGF could modulate the anti-cancer effect of Cyclopamine and induce apoptosis in HT-29 colorectal cancer cells

“…In contrast, BCL2 and Cyclin D1 gene expression were not decreased in our study by cyclopamine treatment. Although Cyclin D1 is typically thought of as an oncoprotein, more research should be done on the impact of alterations in its expression in various malignancies [17]. Despite the fact that Cyclin D1 expression has been found to rise in many cancers, some researches have suggested that excessive Cyclin D1 expression may inhibit cell proliferation [33].…”

“…Treatment with cyclopamine was associated with an increase in some of apoptotic genes, inhibition of colon formation, a little decline in metabolic activity of cells, and slight increase in apoptotic cells. According to the results of previous studies, Cyclopamine treatment on the colorectal cancer cell lines alters the morphology of cells, reduces viability, impairs cell migration ability, and eliminates chemotherapy resistance [17]. Additionally, it was discovered that cyclopamine decreases the expression of SMO and GLI1, which inhibits the Shh pathway and may potentially decrease the expression of self-renewal genes in colorectal cancer [16].…”

“…Many studies indicate that the Hh signaling pathway participates in the development of CRC [12,13]. Recently, studies have shown that Shh pathway inhibitors such as Cyclopamine can inhibit the growth of cancer cells and also stop the cell cycle and nally induce apoptosis [14][15][16][17]. Cyclopamine is a steroidal alkaloid extracted from the Veratrum californicum plant and identi ed as a teratogen responsible for causing craniofacial birth defects, including one eye, in fetuses born to sheep grazing in the western mountains of the United States [18].…”