Antitumor activity of dictamnine against colorectal cancer through induction of ferroptosis and inhibition of M2 macrophage polarization via the MAPK signaling.

ABSTRACT

Colorectal cancer (CRC) is an aggressive cancer type globally. Surgery and chemotherapy are often ineffective at curing CRC. Dictamnine is a natural product derived from Dictamnus dasycarpus Turcz. root bark and possesses multi-pharmacological properties, including anticancer effects. Nevertheless, the biological roles and the possible mechanism of dictamnine in CRC are still unclear. Here, we demonstrated that dictamnine blocked cell viability and proliferation in DLD-1 human colorectal adenocarcinoma cells and LoVo human colon cancer cells. Dictamnine triggered CRC cell ferroptosis, as evidenced by enhanced levels of reactive oxygen species, malondialdehyde, and Fe2+ levels, alongside downregulation of glutathione peroxidase 4 protein expression. In addition, CD163 (HPA ID HPA046404) was highly expressed and CD68 (HPA ID CAB000051) was lowly expressed in CRC tissues and CRC cell culture medium-cultured THP-1 monocytes-derived macrophages. The patients with CD163 low-expression lived much longer than those with CD163 high-expression, indicating that M2 polarization of macrophages was related to poor prognosis of CRC. Dictamnine markedly inhibited CD163 protein expression, transforming growth factor-ß and arginase 1 mRNA expressions and IL-10 production in macrophages with CRC cell co-culture, suggesting that dictamnine impeded M2 polarization of macrophages. Mechanistically, dictamnine repressed ERK phosphorylation in CRC cells. The treatment with the ERK activator tBHQ counteracted the effects of dictamnine on CRC cell proliferation and ferroptosis, as well as its inhibitory effect on M2 polarization of macrophages. Results of a xenograft model showed that dictamnine effectively hindered CRC tumor growth in vivo. Collectively, these data provide evidence for the clinical trials of dictamnine as a novel drug for CRC therapy.