Low-dose carbon monoxide suppresses metastatic progression of disseminated cancer cells

• Published in: Cancer letters Vol. 546; p. 215831
• Main Authors: Zhang, Tiantian, Zhang, George, Chen, Xiang, Chen, Zhengming, Tan, Adrian Y., Lin, Anthony, Zhang, Cheryl, Torres, Lisa K., Bajrami, Sandi, Zhang, Tuo, Zhang, Guoan, Xiang, Jenny Z., Hissong, Erika M., Chen, Yao-Tseng, Li, Yi, Du, Yi-Chieh Nancy
• Format: Journal Article
• Language: English
• Published: Clare Elsevier B.V 10.10.2022; Elsevier Limited
• Subjects: Animal models; Antibodies; Breast cancer; Cancer; Carbon monoxide; Cell culture; Cell migration; Clinical trials; CYP1B1; Fibronectin; Heme; Kinases; Liver cancer; Lung cancer; Metastases; Metastasis; Mouse models; Pancreatic cancer; Patients; Prostate cancer; Proteins; Tumor cell lines; Tumors; pQ; NSG; PNET; Metastasis; CO; FPKM; GESA; LC-MS; PDAC; TCA; Mouse models; HRG1; RNA-Seq; SP1; Heme; TGL; CYP1B1; CORMs; TNBC
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2022.215831

Low-dose carbon monoxide (CO) is under investigation in clinical trials to treat non-cancerous diseases and has an excellent safety profile. Due to early detection and cancer awareness, an increasing number of cancer patients are diagnosed at early stages, when potentially curative surgical resection can be done. However, many patients ultimately experience recurrence. Here, we evaluate the therapeutic effect of CO on metastatic cancer progression. We show that 250 ppm CO inhibits the migration of multiple types of cancer cell lines, including breast, pancreatic, colon, prostate, liver, and lung cancer and reduces the ability to adhere to fibronectin. We demonstrate that in mouse models, 250 ppm inhaled CO inhibits lung metastasis of breast cancer and liver metastasis of pancreatic cancer. Moreover, low-dose CO suppresses recurrence and increases survival after surgical removal of primary pancreatic cancer in mice. Mechanistically, low-dose CO blocks transcription of heme importers, leading to diminished intracellular heme levels and a heme-regulated enzyme, cytochrome P4501B1 (CYP1B1). Either supplementing heme or overexpressing CYP1B1 reverses the anti-migration effect of low-dose CO. Taken together, low-dose CO therapy inhibits cell migration, reduces adhesion to fibronectin, prevents disseminated cancer cells from expanding into gross metastases, and improves survival in pre-clinical mouse models of metastasis. •Development of a spontaneous metastasis mouse model of pancreatic cancer.•Low-dose CO prevents disseminated cancer cells from expanding into gross metastases.•Low-dose CO has therapeutic benefit as an adjuvant cancer therapy.•Low-dose CO lowers intracellular heme levels by downregulating heme transports.