Naturally occurring K vitamins inhibit pancreatic cancer cell survival through a caspase-dependent pathway
Shayna L Showalter1, Ziqiu Wang, Christina L Costantino
1Department of Surgery, Jefferson Center for Pancreatic, Biliary and Related Cancers, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Background And Aims:
Available medical therapies against pancreatic cancer are largely ineffective and have many side-effects. Physiologically, vitamins K1 and K2 (VK) act as co-factors for gamma-carboxylation of prothrombin and other coagulation factors. In previous studies, VK analogs have been found to have potent negative effects on the survival of various cancer cells. We hypothesized that the well-tolerated and naturally occurring VK1 and VK2 may be used to inhibit pancreatic cancer cell survival.
Methods:
Four pancreas cancer cell lines were tested. Two of these (MiaPaCa2 and PL5) were found to be sensitive to VK1 and VK2 (IC50 values < or =150 microM). To address the mechanisms of this effect on cell survival, we performed cell cycle and apoptosis studies using VK2 (the more potent compound).
Results:
We found that VK induced caspase-dependent apoptosis in over 60% of cells in the sensitive lines at the half maximal inhibitory concentration (IC(50)) range. Further, this induction in apoptosis was antagonized by a caspase inhibitor. Accompanying apoptosis, a dose- and time-dependent induction of extracellular signal-regulated kinase (ERK) phosphorylation occurred when sensitive lines were treated with either VK1 or VK2 at inhibitory doses. Simultaneous co-treatment of cells with a MEK1 inhibitor and VK prevented both the induction of ERK phosphorylation and the apoptosis, showing that the mitogen-activated protein (MAP) kinase pathway is central for VK-mediated apoptosis in pancreatic cancer cells.
Conclusion:
These data show that naturally-occurring, non-toxic K vitamins can inhibit the survival of some pancreatic cancer cell lines. These novel, safe and clinically-utilized agents initiate a caspase-dependent apoptosis via the MAP kinase pathway and could potentially benefit patients with pancreatic cancer either as a single agent or in combination with chemotherapy for treatment, or for prevention of recurrence of pancreas cancer post resection.
Insights
Naturally occurring Vitamin K1 and K2 (VK) show potential in inhibiting pancreatic cancer cell survival by inducing apoptosis. These safe vitamins may offer new therapeutic options for pancreatic cancer patients.
Area of Science:
- Oncology
- Cell Biology
- Nutritional Science
Background:
- Pancreatic cancer treatments are largely ineffective and cause significant side effects.
- Vitamins K1 and K2 (VK) are essential co-factors for coagulation and have shown anti-cancer effects in prior studies.
- Naturally occurring VK1 and VK2 are well-tolerated and were investigated for their potential to inhibit pancreatic cancer cell survival.
Purpose of the Study:
- To investigate the efficacy of Vitamins K1 and K2 (VK) in inhibiting pancreatic cancer cell survival.
- To explore the underlying mechanisms of VK-induced apoptosis in pancreatic cancer cells.
Main Methods:
- Four pancreatic cancer cell lines were tested for sensitivity to VK1 and VK2.
- Cell cycle and apoptosis studies were conducted using VK2 on sensitive cell lines.
- Mechanisms involving caspase activation and the MAP kinase pathway (ERK phosphorylation) were analyzed.
Main Results:
- Two cell lines (MiaPaCa2 and PL5) demonstrated sensitivity to VK1 and VK2 (IC50 ≤ 150 μM).
- VK treatment induced caspase-dependent apoptosis in over 60% of sensitive cells.
- VK-induced apoptosis was mediated through the MAP kinase pathway, involving ERK phosphorylation.
Conclusions:
- Naturally occurring, non-toxic Vitamins K1 and K2 can inhibit the survival of certain pancreatic cancer cell lines.
- These vitamins induce caspase-dependent apoptosis via the MAP kinase pathway.
- VK may serve as a novel therapeutic agent, alone or in combination with chemotherapy, for pancreatic cancer treatment or recurrence prevention.
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