I have already posted about parthenolide, extracted from feverfew, a traditional daisy-like medicinal plant used mainly in the treatment of migraines. See my page on parthenolide on the right-hand side of my homepage for more details. I have been following this research for a while, now. And I finally have an interesting update. This morning I received a Google Alert concerning a parthenolide water-soluble analog called dimethylamino-parthenolide (or DMAPT for short), which swiftly kills leukemic stem cells (LSCs) from both myeloid and lymphoid leukemias, and is also highly cytotoxic to bulk leukemic cell populations. Molecular studies indicate the prevalent activities of DMAPT include induction of oxidative stress responses, inhibition of NF-kB, and activation of p53. The compound has approximately 70% oral bioavailability [ ]. I took this from the abstract, which is publicly available at: http://tinyurl.com/2ytvoa

Thanks to a close friend (grazie!), I was lucky enough to get my hands on the full study, which was published in Blood on September 5, 2007. Here are a few of the more relevant excerpts. LSCs, the study tells us, are dormant and for that reason do not respond to chemotherapy, which targets only active cells. This is probably why relapses occur. Another problem with conventional leukaemia chemotherapy is that it is very toxic to normal stem cells. Not good.

Previous studies, the researchers point out, show that NF-κB, a known regulator of growth and survival, is constitutively active in LSCs but not in normal hematopoietic stem cells (HSCs). Notably, many traditional cancer therapies induce activation of NF-κB, a potentially undesirable characteristic likely to facilitate survival of malignant cells. Now, this is fascinating. I didn’t realize that some conventional chemotherapy actually ACTIVATES NF-κB! Gee whiz. That is not good at all.

The study also reports that it is not enough to inhibit NF-κB in order to induce apoptosis in acute myelogenous leukaemia. The tumor suppressor gene p53 needs to be activated, and oxidative stress must also be induced by boosting the levels of reactive oxygen species (ROS) to the point where the cell simply cannot survive any longer (as I understand it). The researchers report that their data suggest that the mechanism of LSC death involves combined inhibition of survival pathways and activation of tumor suppressor and/or stress pathways. They also discuss one of their previous findings, i.e., that the robust apoptosis of primary AML cells can be achieved with a single agent, the plant derived compound parthenolide (PTL), which is known to induce oxidative stress and inhibit NF-κB. Importantly, PTL also effectively eradicates AML stem and progenitor cells in vitro while sparing normal hematopoietic cells. So, parthenolide, or PTL for short, kills acute myelogenous leukemia cells (AML), including AML stem cells, but does not affect normal stem cells. I had actually already mentioned that (see my page), but it’s always good to repeat things, sometimes.

As we have seen happen with other compounds such as curcumin, though, PTL is poorly absorbable. So the researchers tested several PTL analogs, finally identifying DMAPT, which is over 1000 fold greater solubility in water relative to PTL. Wow! The study continues: DMAPT effectively eliminates human AML stem and progenitor cells without apparent harm to normal hematopoietic stem and progenitor cells. The compound also eradicates phenotypically primitive blast crisis CML and acute lymphoblastic leukemia (ALL) cells. Excellent.

The lab tests were performed using primary human AML, CML, ALL cells, and normal bone marrow (BM) cells. For those who are more scientifically-minded, DMAPT was prepared from the reaction of parthenolide with dimethylamine, and the resulting dimethylamino analog was then converted to its water-soluble fumarate salt.

DMAPT was found to induce the apoptosis of dormant leukemic stem cells as well as rapidly dividing active leukemic cells. This is important, of course. Researchers tested DMPAT also on three dogs with advanced CD34-positive spontaneous leukaemia. The dosage, 50-100 mg per kilo, was well tolerated, and the results showed obvious in vivo activity of DMPAT on the dogs’ leukaemic stem cells through inhibition of NF-κB and induction of oxidative stress.

The study ends by stating that Taken together, the data indicate that DMAPT mediates in vivo biological changes in leukemia cells that will lead to their impairment and/or death. Moreover, given the strong efficacy of the drug for AML stem and progenitor cells in vitro, we propose that a similar effect is possible in vivo, and provide preliminary evidence that LSC-specific targeting can occur in spontaneous canine leukemia. Based on these preclinical findings, its oral bioavailability, and a favorable toxicology profile, DMAPT is proceeding to human phase I clinical trials in the near future.

And in fact, according to a recent University of Rochester Medical Center news release (http://tinyurl.com/28l75m), clinical trials are set to begin in England before the end of the year. Oh, and by the way, DMAPT seems to have an effect on multiple myeloma cells, too, according to Monica Guzman, one of the main researchers. YIPPEE, I say!