Taking supplements with CD4/6 inhibitors - what does research show?

Palbociclib, Ribociclib and Abemaciclib are CD4 and CD6 inhibitors and patients taking these drugs are commonly told by their oncologist not to take supplements. Is this correct? The truth is far more concerning.

CDK, or cyclin-dependent kinase is important for cell division, and two enzymes CD4 and CD6 can stimulate cancer cell proliferation. CD4/6 inhibitors aim to block this.

Three drugs are increasingly being used with breast cancer (in women and men), metastatic breast cancer and liposarcoma, The aim is to increase the survival time before the cancer spreads.

Ibrance, or Palbociclib

Kisqali, or Ribociclib

Verzenio, or Abemaciclib 

What are the common side-effects of CD4 and CD6 inhibitors?

Manufacturers claim that the side-effects with CD4/6 inhibitors are less severe than with typical chemotherapy drugs. WebMD and Drugs.com list common side effects as fatigue, gastrointestinal disturbances, such as nausea, diarrhoea, and vomiting. Bone marrow suppression may also occur along with neutropenia and leukopenia. Anaemia and thrombocytopenia occur only occasionally.

Can you take supplements with these drugs?

One of CANCERactive’s patients (in Canada) was told by her oncologist that she must not take supplements with Ibrance. She checked this with the Hospital Pharmacist. She wanted to take supplements such as Turmeric, Berberine and milk thistle. Neither the Pharmacist nor the oncologist could produce any studies, so our patient rang Pfizer and asked to speak to someone who worked on Ibrance. The scientist at Pfizer was asked if she could take a list of certain supplements, and he said … “No problem”. In reality, she had no problems; her supplements restricted the side-effects. So what’s the Truth?

CD4/CD6 inhibitors in the UK

A recent patient was told two things - supplements such as berberine affect the CD4 and CD6 enzymes and will block the action of the drugs; and supplements such as fish oils will increase blood thinning as these drugs are blood thinners. Let us examine these two potential issues.

i) Some supplements such as Berberine negatively affect the CDK enzymes?

An internet search showed a dearth of evidence that this was true.

Berberine - One study (1) showed that Berberine had positive benefits with CD4 (and CD8) stating “This study highlighted the benefits of berberine administration as antibiotic adjuvant in E. coli sepsis”.

A second study, again referring to the immune system and infection talked of, “A Berberine-like protein, which is expressed during immunity, specifically oxidises CDs with a preference for longer fragments (CD4-CD6). Oxidised CDs show a negligible elicitor (foreign body) activity and are less easily utilised as a carbon source by the fungus Botrytis cinerea”. Although this is a plant study it means that a berberine-like compound is inhibiting CD4 and CD6, preventing their use by a foreign body.

A third in vitro study (3) showed that targeting CD6 disrupted CD4 cells, and increasing doses of CD6 inhibitors caused a loss in anti-inflammatory action.

Finally, to continue our ‘clutching-at-straws-because-there-is-no-real-research’ theme, in psoriasis, CDC6 seems to cause proliferation making it worse, and berberine helps block this (4).

So if anything, you might conclude Berberine and CD4/6 inhibitors are on the same team. 

Similarly, there is nothing of note about Turmeric, Honokiol, Dandelion, Vitamin D3 and CD4/CD6 interactions in PubMed or on Internet search.

OK. So what if anything should you be avoiding? Well, it’s not those dodgy supplements but certain foods and drugs.

ii) CD4/CD6 inhibitors are blood thinners so you must not take other thinners such as supplements of fish oils, turmeric, ashwagandha and aspirin

There appears to be no evidence that these 3 drugs are blood thinners.

With Ribociclib, low white blood cell counts Neutropenia) are common during its use. This is not the same as blood thinning. Fish oils, for example, will not lower white cell counts, nor will turmeric which occasionally might lower platelets.

Similarly Abemaciclib and Palbociclib. There is no mention in PubMed or or search engines of any of these 3 drugs being blood thinners.

So what should you be careful of doing?

Palbociclib is a time dependent inhibitor of CYP3A; If you take other inhibitors of CYP3A - something we have told you about frequently in the past (See HERE) - you can concentrate this type of drug. Similar warnings appear on the Ribociclib and Abemaciclib websites.

For example, the often used off-label drug Itraconazole can concentrate blood levels of Ibrance by 87% according to Pfizer. Other drugs that should not be taken at the same time ass CD4/CD6 inhibitors are clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole. Of the 27 drugs added to the list since 2008, 13 of them can potentially cause ‘Sudden Death’ according to the Lawson Health Institute in Canada.

Then there are foods - Grapefruit, grapefruit juice, Seville Oranges and pomelo. These all contain furanocoumarins, which are metabolised by CYP3A4 to compounds that bind to and block the active site of the enzyme, causing irreversible deactivation.  

Did your oncologist warn you of this?

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References

1. Potential application of berberine in the treatment of Escherichia coli sepsis; Elisa Pierpaoli et al; Nat Prod Res; 2021 Nov;35(22):4779-4784. 

2. An Arabidopsis berberine bridge enzyme-like protein specifically oxidizes cellulose oligomers and plays a role in immunity; Federica Locci et al; Plant J, 2019 May;98(3):540-554.

3. Modulation of CD4 T cell function via CD6-targeting; Raquel Filipa Freitas et al; EBioMedicine, 2019 Sep;47:427-435.

4. Berberine downregulates CDC6 and inhibits proliferation via targeting JAK-STAT3 signaling in keratinocytes; Shuna Sun et al; Cell Death Dis, 2019 Mar 20;10(4):274.

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