Vitamin K Studied in Treatment and Prevention of Liver Cancer
Division of Cancer Biology
Hepatocellular carcinoma (HCC), the most common type of primary liver tumor, is often found at an advanced stage and available treatments rarely offer a cure once the cancer has spread. There remains an urgent need for agents that can more effectively treat HCC or prevent liver cancer development.
Brian Carr, M.D., Ph.D., professor of medical oncology at Thomas Jefferson University’s Kimmel Cancer Center, has been exploring the use of vitamin K1 (simply called vitamin K in the United States) and synthetic derivatives of the compound for the treatment of HCC for over 15 years.
He first became drawn to the potential use of vitamin K in the treatment of HCC after reading the results of studies testing biomarkers to detect liver cancer. Alpha-fetoprotein, commonly used as a biomarker for HCC, is only expressed by 50% of those tumors. In contrast, an immature form of prothrombin (a protein involved in blood coagulation), called DCP, is secreted by about 80% of HCCs.
“A known function of vitamin K in mammals is helping convert the immature protein DCP to mature prothrombin and this mechanism is broken in patients with HCC,” explained Dr. Carr. His laboratory began treating HCC cells with large doses of vitamin K. They observed that these doses restored normal prothrombin production in the cancerous cells and “the natural vitamin K, which corrected this defect, also stopped the cancer cells from growing,” Dr. Carr said. He also conducted a phase I/II study* of vitamin K and found no toxicity at doses up to 1,000 mg/day.
With funding from NCI** , Dr. Carr’s laboratory collaborated with synthetic chemists to develop and test several derivatives of vitamin K, the most potent of which was called compound 5 (Cpd5). Cpd5 not only stopped cancer cells from growing—a cytostatic effect—it killed them, a cytotoxic effect. This cell-killing effect was caused by over-stimulation of a cell-signaling molecule called extracellular receptor kinase (ERK), which shut down the cell-growth machinery.
Unfortunately, research in animal models showed that the effective dose and the toxic dose of Cpd5 were too close to each other, rendering Cpd5 unsuitable for human clinical trials. However, the recent development of mainstream cytostatic cancer drugs “made me realize that the paradigm we’ve had for the last 40 years of cancer treatment, of killing cancer cells, may be inadequate,” Dr. Carr said. “Instead of looking for more and more potent compounds, which kill normal cells as well as cancer cells, maybe we need to focus on blocking selected signaling pathways in HCC cells.”
The Carr laboratory recently turned back to studying natural vitamin K, this time with the cytostatic drug sorafenib (Nexavar®). In preliminary in vitro and in vivo work, the addition of vitamin K significantly enhanced the effects of sorafenib and reduced the dose required to affect cell growth in both HCC*** and pancreatic cancer****.
*Carr BI. Suppression of DCP/PIVKA-2 and alpha-fetoprotein levels in human hepatocellular carcinoma (HCC) by high doses of vitamin K1 (VK1). Hepatology 1996;348A.
**Grant Number: 5R01CA082723-09
***Wei G, Wang M, Hyslop T, Wang Z, Carr BI. Vitamin K enhancement of sorafenib-mediated HCC cell growth inhibition in vitro and in vivo. International Journal of Cancer, June 7, 2010;[Epub ahead of print]
****Wei G, Wang M, Carr BI. Sorafenib combined vitamin K induces apoptosis in human pancreatic cancer cell lines through RAF/MEK/ERK and c-Jun NH2- terminal kinase pathways. Journal of Cell Physiology,July 2010;224(1):112-9.