Order Matters

By Jacob Schor, ND

Photo by Kanko* via Flickr, used under the Creative Commons License.

If order matters, what comes first?

The implications of a study published way back in February in Clinical Cancer Research have been stewing around in the back of my mind. It’s one of a growing cascade of studies in which researchers at fairly mainstream medical institutions reveal that they’ve been playing with stuff that’s standard fare on a naturopathic doctor’s dispensary shelves.

In this instance we are talking about researchers from the Mayo Clinic in Minnesota playing with various combinations of curcumin, an extract of turmeric and green tea, and seeing how they affect lymphocytic leukemia cells.

As much as we still occasionally hear and read the myopic criticisms of our profession that claim our therapies are not backed by research, this study is just one of many. A PubMed search just now of the National Library of Medicine’s published scientific literature on curcumin and cancer yields a list of 1,265 articles. A search on green tea and cancer yields 1,338 published papers in the peer reviewed journals.

This particular study was similar to many others; cancer cells were grown in a laboratory, exposed to the ‘natural’ ingredient, and the degree to which growth was slowed down or that cancer cells were inspired to drop dead was measured. In this particular experiment, chronic lymphocytic leukemia B cells were the targets. Nothing unique about this setup.

And no surprise that the curcumin was found potentially useful. Here let me quote from the results in the abstract and then translate the interesting parts:

“Curcumin induced apoptosis in CLL B cells in a dose-dependent (5-20 micromol/L) manner ...”

‘Apoptosis’ is when a cell decides life isn’t worth living and self-destructs. Curcumin convinces these leukemia cells to commit suicide. The more curcumin added to the cells, the more died.

“Coculture of CLL B cells with stromal cells … decreased sensitivity to curcumin.”

Adding some other cells, stromal cells, into the mix decreased the curcumin effect; fewer cancer cells died.

“When curcumin was administered simultaneously with EGCG [green tea], antagonism was observed for most patient samples.”

Adding green tea extracts along with curcumin to the mix of leukemia and stromal cells caused, what these scientists called ‘antagonism.’ That’s an odd term and you need to view the full text article to get an idea of what they mean by antagonism. Put simply, the combination of the two natural substances, green tea and curcumin, didn’t work as well as predicted: “… simultaneous culture had a less than additive effect.” That is if you measure the anti-cancer effect of each substance separately, you can add the two ‘effects’ together to predict what should happen when both are used simultaneously. It turns out they don’t work as well as predicted; they antagonize each other.

“In contrast, sequential administration of these agents led to substantial increases in CLL B-cell death ...”

When instead of adding both curcumin and green tea to the culture at the same time, the cells are instead exposed to one agent and then the other, the story changes completely. They tried treating the cells first with curcumin followed by green tea, and vice versa. To quote the authors, “… sequential administration led to dramatically more leukemic cell death than simultaneous administration.”

Not only did exposing the cancer cells to these substances one at a time matter, but order mattered as well. Green tea first, followed by curcumin, worked much better than if the cells were exposed to curcumin first.

Think about the implications this brings to our practices. Sequential administration of treatments may work better than simultaneous treatments. Order matters. In this case green tea works better first.

Typically in practice we pile a bunch of different substances into a patient’s blood stream on the assumption that each has a specific action and these effects will add together. This reminds me of those combination locks that have four or five parallel numbered rings and to open the lock. You line up a number on each ring, get all the right numbers in a row at the same time, and the lock opens.

This leukemia study makes that image obsolete. If sequence matters, just knowing the combination is no longer enough. This is more like the dial lock on a safe. Sequence is essential. Three turns to the left and stop on the right number, then turn the dial to the right past your first number and stop on another specific number. And so on…

Think about this: our cancer patients often take a long list of supplements. This study suggests that, at least in chronic lymphocytic leukemia, we should start them on green tea for a period of time and then switch to curcumin. What if it is a similar story with quercetin, resveratrol, sulforaphane, vitamin D, melatonin and so on? What if there is a ‘best sequence’ for all of these? What if that combination were to vary by cancer? By patient? Or even by dose?

This is worth stewing about. It makes me think of certain patients who tell me they vary what supplements they take day-to-day based the way a pendulum held in their hand swings. Though this sounds less than ideal, it can’t work any worse than flipping a coin to decide on a sequence, which for the time being may still be of some utility.

Now that this study has been published, we shouldn’t be surprised to see other studies up asking this question: “If order matters, what comes first?”

Ghosh AK, Kay NE, Secreto CR, Shanafelt TD. Curcumin inhibits prosurvival pathways in chronic lymphocytic leukemia B cells and may overcome their stromal protection in combination with EGCG. Clin Cancer Res. 2009 Feb 15;15(4):1250-8.