Polycythemia vera (PV) is an acquired, clonal stem cell, myeloproliferative, hematological disorder with variable increase in erythrocytes, neutrophils and granulocytes. PV causes significant morbidity and mortality from thrombotic and hemorrhagic complications and has a propensity for leukemic transformation. Phlebotomy, interferon a and myelosuppressive chemotherapy have been the cornerstones of treatment to date. With no specific drugs to treat PV effectively, the development of new therapeutic modalities is important. A somatic mutation in the JAK2 tyrosine kinase (V617F) causing constitutive activation of the JAK/STAT pathway was recently reported in over 80% of PV patients. Based on this observation, we explored the therapeutic efficacy of tyrosine kinase inhibitors (TKIs) such as imatinib (
Gaikwad A et al, Blood 106: 2601, 2005
) and AMN107 for PV. These TKIs showed marginal efficacy in vitro. Research using natural sources has led to important pharmacological targets for cancer therapy. Several plant molecules have either been introduced to the US market or are in late-phase clinical trials. We focused on a natural product called “Avicin D,” which is a plant derived triterpene electrophilic molecule with cyto-protective and anti-inflammatory functions (Haridas V et al, J. Clin. Invest 113: 65, 2004
; Haridas V et al, PNAS, 98:11557, 2001
). Avicin D is reported to initiate selective pro-apoptotic activity in malignant cells (Mujoo K, et al. Cancer Res. 61: 5486, 2001
) by direct perturbation of mitochondria (Haridas V, et al. PNAS, 98: 5821, 2001
). It has also been shown to down-regulate a group of pro-survival, anti-apoptotic proteins that act downstream of cytochrome c release, including HSP70, HSP90 and XIAP (Gaikwad A, et al. Clin. Cancer Res. 11: 1953Gaikwad A, et al. Clin. Cancer Res. 11: 2005). In addition, Avicin D also blocks glycolysis, a key metabolic process that malignant cells exploit for their proliferation and survival (Warburg phenomenon). To examine Avicin D’s therapeutic efficacy for PV, we utilized mouse reporter cells expressing the JAK2 V617F protein. Avicin D inhibited the growth of these cells with an IC50 of 2μM. Interestingly, in cells carrying wild-type JAK2 there was no significant inhibitory effect. In addition, Avicin D showed marked growth inhibition of human erythroleukemic cells (HEL) that harbor the JAK2 V617F mutation at an IC50 of 2μM. We then examined Avicin D’s effect on in vitro expanded native human erythroid progenitor cells. Avicin D showed specific growth inhibition of erythroid progenitor cells from PV patients (IC50 ~3μM) with no significant effect on the normal progenitors. We conclude that Avicin D should be a promising candidate for clinical trials of PV and other disorders that are associated with JAK2 V617F somatic mutations.
Disclosure: No relevant conflicts of interest to declare.
