Palbociclib, Ribociclib and Abemaciclib are CD4 and CD6 inhibitors and patients taking these drugs are commonly told by their oncologist not to take supplements because of contraindications. Is this correct?
CDK, or cyclin-dependent kinase, is important for cell division, and two enzymes CD4 and CD6 can stimulate cancer cell division and proliferation. CD4/6 inhibitors aim to block this.
Three drugs are increasingly being used with early breast cancer (in women and men), later metastatic breast cancer, and liposarcoma, The aim is to increase the survival time before the cancer spreads. In breast cancer the drugs are often given with an aromatase inhibitor such as Anastrozole, Letrozole or Fulvestrant. There are three drugs in common use -
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 had 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? We conducted an extensive review of PubMed.
CD4/CD6 inhibitors in the UK
A recent patient was told two things involving contraindications - 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. In fact, Berberine seems to be on the same team as the three drugs.
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 (2), 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 actually inhibiting CD4 and CD6, preventing their use by a foreign body. It works in the same way as our three drugs!
A third in vitro study (3) showed that targeting CD6 disrupted CD4 cells, and increasing doses of CD6 inhibitors caused a loss in inflammatory action.
Finally, to continue our ‘clutching-at-straws-because-there-is-no-real-research’ theme, in psoriasis, CD6 seems to cause proliferation making it worse, and berberine helps inhibit 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 contraindications in PubMed or on Internet search.
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 anywhere that these three 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 either of these two drugs being blood thinners.
OK. So what if anything should you be avoiding? Well, it’s not those dodgy supplements but actually certain foods and drugs.
iii) What should you be careful of?
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, 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 these?
iv) Phycocyanin and CD4/6 inhibitors
The aim of these drugs is to keep cancer at bay, for longer. One of our patients had taken Ibrance for almost 7 years. Her oncologist asked what supplements she was taking. In all about eight. Her oncologist noted Phycocyanin, which he'd never heard of, and said he would check it out. At the next visit, the oncologist told our patient that from what he'd read, he thought Phycocyanin would enhance Ibrance.
According to a 2024 review, part of the action of these drugs in restricting cell division and spread (5) is CDK inhibition. p27 and p21 can also achieve this. Another action is the anti-inflammatory effect.
Phycocyanin is an active compound extracted from algae, and has outstanding antioxidant and anti-inflammatory actions (6). It has a number of research studies with breast cancer. It can only enhance our three drugs.
Indole 3 carbinol is often used as a natural compound against Er+ve breast cancer. One of its substrates, DIM, is known to have action with p27.
Go to: Phycocyanin - a marine anti-cancer agent
v) Taking the drug 'for as long as it works'
What your oncologist is telling you is that you can expect chemo-resistance to block the dug from working after some time (usually around two years). Berberine, turmeric and melatonin and known to reduce chemo-resistance. However, usually chemo-resistance is caused by the build up of Galectin-3 inside the cancer cell. Modified Citrus Pectin is known to block Galectin-3 build up. Also putting 2-3.6 gm of organic turkey tail powder in your daily green juice/smoothie is know to make the drugs more effective for longer, to keep up levels of your white cells and to improve survival times.
Go to: Modified Citrus Pectin and cancer
Go to: Turkey Tail Mushroom in cancer treatment
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References
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Potential application of berberine in the treatment of Escherichia coli sepsis; Elisa Pierpaoli et al; Nat Prod Res; 2021 Nov;35(22):4779-4784.
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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.
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Modulation of CD4 T cell function via CD6-targeting; Raquel Filipa Freitas et al; EBioMedicine, 2019 Sep;47:427-435.
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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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The Role of CD4/6 Inhibitors in Breast Cancer Treatment; Luv Purohit et al; Int J Mol Sci. 2024 Jan 19;25(2):1242.
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Phycocyanin: Anti-inflammatory effect and mechanism; Runze Liu et al; Biomed Pharmacother
. 2022 Sep:153:113362.
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