Exploring How an Antitumor Drug Kills Invasive Colorectal Cancer Cells

Fengzhi Li, PhD

Dr. Fengzhi Li is leading research to demonstrate a “proof of principle” and mechanism of action for the novel anticancer drug FL118 is preferable to kill drug resistant colon cancer cells, while protecting normal cells from FL118-induced cancer cell-killing effects.

It is known that overexpression of cancer cell survival-associated proteins such as survivin, Mcl-1, XIAP and cIAP2 would make cancer cells be highly resistant to treatment (drug or radiation). In this regard, we have identified a novel compound (designated FL118) that could selectively downregulate survivin, Mcl-1, XIAP and cIAP2 in cancer cells and shows superior antitumor activity. Importantly, these effects are p53 status-independent.

In other words, FL118 could inhibit the expression of survivin, Mcl-1, XIAP and cIAP2 in cancer cells regardless of cancer cells with wild-type p53, mutant p53 or null p53. Consistent with these observations, FL118 could effectively eliminate colon cancer in xenograft models no matter the tumor cells have wild-type p53, mutant p53 or null p53. Why is this important?
Wild-type p53 is an important tumor suppressor protein. Loss or mutation of p53 proteins contributes to tumorigenesis and cancer progression. Relevant to this project, the advanced later stage of colorectal cancer usually has mutant or null p53, which makes these later stages of colon cancer be difficult to treat, due to treatment resistance.

Therefore, most of the current FDA-approval drugs are ineffective to treat cancer with mutant or null p53. In this regard, FL118 provides a potential excellent option for treatment of these types of colon cancer. Elucidation of the FL118 mechanism of action to kill cancer cells and protect normal cells is very important for correct use of this antitumor agent for treatment of colorectal cancer as well as possible other cancer types.