Published online Feb 24, 2024. doi: 10.5306/wjco.v15.i2.317
Peer-review started: October 9, 2023
First decision: November 23, 2023
Revised: December 6, 2023
Accepted: January 8, 2024
Article in press: January 8, 2024
Published online: February 24, 2024
Processing time: 133 Days and 17.4 Hours
Colorectal cancer (CRC) is one of the most common types of cancer globally. In the last few decades, research efforts have been directed towards understanding the cellular and genetic mechanisms underlying the development and progression of CRC. This has led to the identification and study of a specific subset of cells within colorectal tumors, known as cancer stem cells or cancer stem-like cells (CSCs). The concept of CSCs originated in the mid-20th century but was not widely accepted until the late 1990s. The idea behind CSCs is that a small proportion of cancer cells within a tumor have stem cell-like properties, including the ability to self-renew and differentiate, which contribute to tumor initiation, progression, metastasis, and recurrence. They are also often associated with resistance to traditional cancer therapies.
Several studies have suggested that limonin, a natural compound found in citrus fruits, can exert anti-tumor effects. These effects appear to be due to multiple mechanisms, including the induction of apoptosis (programmed cell death), the inhibition of cancer cell proliferation, and the suppression of metastasis. Based on this, we then investigated whether it exerts suppressing effects on CSCs.
In this research, we evaluated the effects of limonin, a natural compound which is one of the most abundant active ingredients of Tetradium ruticarpum on stemness of CSCs derived from colorectal carcinoma cells. We also investigated the potential mechanism of limonin on stemness of CSCs.
We performed cellular experiment to verify the suppressing effects of limonin on CSCs and performed animal experiment to verify its effects in vivo.
Limonin was found to have suppressive effects on CRC cell activities, which included cell growth, movement, invasion, colony growth and tumor development in soft agar. Even at relatively low concentrations, limonin reduced the expression of stemness markers such as Nanog and β-catenin, decreased the percentage of aldehyde dehydrogenase 1-positive CSCs, and lowered the rate of sphere formation, showing that limonin hinders stemness without cytotoxicity. Furthermore, the treatment of limonin reduced invasion and tumor development in soft agar and in nude mice. Also, limonin treatment notably inhibited the phosphorylation of STAT3 at Y705 but not S727 and had no effect on total STAT3 expression. The limonin-induced reduction in Nanog and β-catenin expression and sphere formation was noticeably offset by a pretreatment with 2 μmol/L colievlin.
In summary, the findings suggest that limonin holds potential as a compound targeting CSCs, and might be utilized for tackling the recurrence and metastasis of CRC.
Can limonin to be used as a chemotherpeutic sensitizor?