TKI’s: An Existing Example of Chemotherapeutic Drug Induced Acute, Delayed, and Permanent Thyroid Problems. Can FQ’s Act as TKI’s?


Tyrosine Kinase Inhibitors (TKI’s) are relatively recent chemotherapy drugs developed to fight cancer.  Since their use, it’s become apparent that one of the adverse effects of TKI’s is that they may affect thyroid function or the HPT axis.

Why am I including a separate section of the adverse effects of TKI’s here?  What does that have to do with the fluoroquinolone antibiotics?

For a number of reasons (see “The Tyrosine Connection”), I started questioning as to whether or not the fluoroquinolones, in addition to functioning as topoisomerase inhibitors, may be acting as tyrosine kinase inhibitors as well.  Or, at the very least, are targeting some common pathway these drugs share.    Additional supportive evidence for this could include the fact that there is a patent application for fluoroquinolone derivatives to be used as kinase inhibitors (see link near bottom of page).   Search “tyrosine kinases” to learn more about them; I included a link to a brief introductory video on the receptors on this page here.

From my perspective, there appeared to be striking similarities between thyroid abnormalities occurring with TKI’s and the thyroid abnormalities I suspect may occur with the FQ’s.  Below I provide an excerpt from the paper “Tyrosine kinase inhibitors and modifications of thyroid function tests– a review”.

Please note the following while reading the excerpt:

  • Both of these drugs (TKI’s and FQ’s) function as chemotherapeutic agents, targeting mechanisms involved in rapid proliferation of cells.
  • TKI’s can potentially interfere with different signaling pathways implicated in cell growth. I question whether FQ’s can do the same.
  • There is a wide range of statistics given for abnormal thyroid function tests (TFT) due to TKI use, and many of these statistics are quite high.   14-85% of patients given the TKI Sunitinib developed hypothyroidism. I question whether the same is true due to FQ usage, but is currently unrecognized (nor is it tested for during or after FQ exposure). Anecdotal reports from FQ victims include reports of thyroid abnormalities post FQ exposure.
  • Thyroid function test abnormalities can be transient or permanent, immediate or delayed due to TKI’s. On average, hypothyroidism appeared after 54 weeks. I question whether the same can occur due to FQ use. Anecdotal reports from FQ victims include reports of hypothyroidism, with varying ranges of time for diagnosis.
  • Some thyroid abnormalities had a biphasic evolution with a decrease in TSH, which could correspond to a thyrotoxicosis status followed by an increase in TSH with TKI usage. I question whether the same could occur due to FQ use, as I describe here.
  • The probability of hypothyroidism increases with time and each cycle of treatment of TKI’s. I question whether the same could be true for susceptible, or possibly all patients exposed to FQ’s.
  • Reported cases of hyperthyroidism have occurred in 25% of patients treated with the TKI Sunitinib. In two subjects, thyrotoxicosis was severe. Anecdotal reports from FQ victims include reports of hyperthyroidism, with varying ranges of time for diagnosis.
  • Destructive thyroiditis has been proposed as one mechanism of TKI-induced thyroid damage. I question whether the same can occur with FQ’s.
  • TSH increases were found to occur in athyreotic (complete absence of thyroid tissue) patients due to TKI usage, as high as five times the upper normal limit. Increases of 210% in the T4 replacement dose occurred in patients while on TKI treatment. I question whether similar TSH fluctuations occur with FQ usage. Anecdotal reports from FQ victims on TH replacement therapy during and after FQ use report loss of TH regulation and extreme fluctuations in medication doses.
  • The majority of TKI patients have a significant reduction of iodine uptake during the ON period of Sunitinib therapy. I question whether the same is occurring with FQ usage, and if so, if this is contributing to thyroid pathology in susceptible FQ victims.
  • Reports of an important inhibition of peroxidase activity have been proposed as a mechanism for TKI-induced thyroid pathology. Sunitinib anti-peroxidase potency could be 25–30% of that of propylthiouracil. This effect could explain the latent period between the initiation of Sunitinib and the development of hypothyroidism. Thus, hypothyroidism could appear only after the release of thyroid hormone reserve of the gland. I question whether something similar to this could occur due to FQ exposure.

Please also note my observation about “coal tar” being a  a common denominator in both  Amiodarone and FQ’s — and therefore FQ-TKI’s (see below) — which may also be a common denominator in both thyroid and mitochondrial dysfunction?  See Paragraph 12 in  Amiodarone Toxicity:  The Closest Thing We Have to “Iodine Toxicity”


From:    Tyrosine kinase inhibitors and modifications of thyroid function tests– a review

Tyrosine kinase inhibitors (TKI) belong to new molecular multi-targeted therapies that are approved for the treatment of haematological and solid tumours.  They interact with a large variety of protein tyrosine kinases involved in oncogenesis.   In 2005, the first case of hypothyroidism was described and since then, some data have been published and have confirmed that TKI can affect the thyroid function tests (TFT) . . . Protein tyrosine kinases (TK) are enzymatic proteins, usually receptors, which catalyse the transfer of phosphate from ATP to tyrosine residues in peptides . . . By targeting several TK receptors, the TKI can potentially interfere with different signalling pathways implicated in oncogenesis.   Since 2005, many authors have reported changes of thyroid function tests (TFT) among patients with different TKI.    In this review, we analyse the effects of four molecules: sunitinib, imatinib, motesanib and sorafenib . . . Among 42 euthyroid subjects  treated by sunitinib for GIST, 62% had an abnormal TSH level: 36% had a persistent hypothyroidism with TSH O7 mU/l and required levothyroxine replacement, 17% had a TSH concentration between 5 and 7 mU/l, and 10% had a TSH suppression.    Since 2006, many authors have reported that sunitinib therapy is associated with hypothyroidism in 14–85% of the patients.    In the study by Mannavola et al. 46% of patients developed hypothyroidism requiring levothyroxine therapy and 25% had a transient elevation of TSH (6).    Rini et al. showed that TFT abnormalities were consistent with hypothyroidism in 85% of the 66 subjects treated for metastatic RCC (7).    Even though some patients really had an increase in their TSH level, they preferentially had a decrease in their free triiodothyronine (fT3) level rather than their free thyroxine (fT4) concentration. . . . In a phase I/II trial focusing on the cardiotoxicity of sunitinib for GIST therapy, Chu et al. found 14% of hypothyroidism defined by high TSH values (9).   On average, hypothyroidism appeared after 54 weeks.  The latest published study prospectively analysed the effects of sunitinib among 59 patients with resistant RCC or with GIST (10).    Its design appears to be the best of all designs in the aforementioned studies since TFT were performed before sunitinib was administered, as well as in the first and last days of each ON period.    Sixty-one per cent of subjects were found to have a transient or permanent elevated TSH, and 27% of them required hormone replacement (10) . . . The probability of hypothyroidism increases with time and each cycle of treatment (5, 6, 10).    In all reported series, TSH concentration increased at the end of the ON phase and was near the normal range at the end of the OFF phase, leading to intermittent hypothyroidism.    After several treatment cycles, baseline TSH levels seemed to increase, revealing a permanent hypothyroidism.    Thus, an ongoing therapy increases the risk of developing hypothyroidism . . . The mechanisms of alteration of TFT during sunitinib therapy are still unclear.    After the publication of Desai et al. sunitinib-induced destructive thyroiditis was advocated (5).    Indeed, in 40% of hypothyroid patients, thyroid abnormalities had a biphasic evolution with a decrease in TSH, which could correspond to a thyrotoxicosis status followed by an increase in TSH.    Furthermore, in two subjects, no thyroid gland could be identified by ultrasound.    Recently, this thyrotoxicosis period preceding hypothyroidism has been reported during the first cycles of therapy (10–12).  Grossmann et al. reported hyperthyroidism in 25% of patients with sunitinib for RCC (12).   In two subjects, thyrotoxicosis was severe.   The increased thyroglobulin level, the decreased iodine uptake, the progression to hypothyroidism and the presence of lymphocytic thyroiditis on fine needle aspiration reinforced the diagnosis of destructive thyroiditis (12).    However, available data remain insufficient to assume that all sunitinib-induced hypothyroidisms are secondary to thyroid destruction . . . Following the study by Desai et al. other physiopathological hypotheses have been proposed.    An iodine uptake inhibition could result in hypothyroidism (6).   The majority of patients have a significant reduction of iodine uptake during the ON period of sunitinib therapy and this reduction is rapidly reversible during the OFF periods.    Iodine uptake blocking could be involved in sunitinib-induced hypothyroidism, as there is a negative relationship between iodine uptake and TSH concentration.    Moreover, the TSH level fluctuates according to the ON or OFF periods.   However, until now, no effect of sunitinib on iodine uptake or on sodium iodide symporter (SLC5A5) has been demonstrated.    An in vitro study even demonstrates the contrary (19).   In FRTL-5 rat thyroid cells, sunitinib inhibited the cellular growth and increased the iodine uptake induced by TSH or forskolin.   This dose-related effect did not appear to be mediated by SLC5A5 as there was no modification of Slc5a5 mRNA expression.    The iodine efflux was not affected either.   Wong et al. reported an important inhibition of peroxidase activity (8).    Sunitinib anti-peroxidase potency could be 25–30% of that of propylthiouracil.  This effect could explain the latent period between the initiation of sunitinib and the development of hypothyroidism.   Thus, hypothyroidism could appear only after the release of thyroid hormone reserve of the gland.   Further research is still required because the links between peroxidase activity and TSH levels have not yet been evaluated. . . . Imatinib-induced modifications of the thyroid function have been studied by de Groot et al.   In 2005, de Groot et al. reported hypothyroidism frequency among ten imatinib-treated patients for medullary thyroid carcinoma (MTC) (22).   Seven of them had undergone thyroid surgery.   One patient was treated for GIST.   Only the seven athyreotic patients (and not the patients with thyroid in situ) had an increased TSH concentration, which approached five times the upper normal value. Hypothyroidism remained subclinical as, even if fT4 and fT3 levels were reduced by 59 and 63% respectively, they remained within the normal range.  The same group assessed the effect of imatinib among 15 subjects with metastatic MTC (23).   In the same way, TSH changes were present only in athyreotic subjects.  The fT4 and fT3 values were not reported, but there was a 210% increase in the levothyroxine replacement dose.   This effect appears rapidly after an initiation of therapy and is reversible, since TSH normalized after discontinuation of imatinib (22). . . . The absorption of levothyroxine did not seem to be impaired by imatinib, since the separate administration of the two medications did not modify TSH levels (22).   The absence of changes in thyroxine-binding globulin and total thyroxine levels neither supports competition for thyroid hormonebinding sites nor supports deiodinase inhibition (22) . . . Many studies clearly have demonstrated that TKI were able to induce disturbances of TFT.   The indications of TKI will probably be broadened and will then increase the number of subjects with thyroid dysfunction.”


The Magnesium Connection

FQ chelation or binding of magnesium, with subsequent disruption of magnesium homeostasis, has long been a major hypothesis in FQ toxicity.   Magnesium is extremely important, being utilized in over 300 enzymatic reactions in the body.   It turns out, all of the known tyrosine kinases require a divalent metal cation for activity, and this is most often magnesium.   TKI’s can cause significant hypomagnesmia in studies, leading to clinical symptoms.    On the other hand, existing low magnesium and cation status can disrupt tyrosine kinase function as well.   Dysglycemia’s, sometimes severe enough to cause “fatal events”, are another well known endocrine adverse effect of the FQ’s, responsible for both pre-market and post market failure of some FQ’s.   The insulin receptor (as well as the IGF-1 or Insulin-Like Growth Factor 1 Receptor) is a tyrosine kinase receptor, and studies have shown a depletion of Mg may cause a defective tyrosine kinase function at the insulin receptor level.    In tendon studies, kinase pathways are strongly affected by FQ’s, as evidenced by significantly reduced amounts of these important signaling proteins at the lowest concentrations of FQ levels studied.    Major neuron-survival pathways include tyrosine kinases.   And they also play a role in regulating the growth and differentiated functions of thyroid cells, and may potentially help regulate the iodine transporter.    Keep in mind that FQ’s target enzymes (topoisomerases) with active site tyrosine residues requiring magnesium and other divalent cations.    I question whether FQ’s will therefore target and promiscuously bind to other important enzymes utilizing tyrosine as a critical residue and Mg or other divalent cations as a cofactor.

Much has been made of FQ’s being “chelating agents” as the cause of their adverse effect profile.   Note that many drugs can complex with metal ions; for example, the antibiotic doxycycline also chelates Ca and Mg, which could also result in a systemic deficit.   Yet, it does not cause the extreme tendon pain or the same “syndrome” that the FQ’s do.   This is one reason why I feel the “Mg-Tyrosine” (along with ATP utilization) combination, important in so many replication, signaling, and receptor processes, may be a target, and not just the loss of Ca or Mg itself.  See references below for a brief introduction to magnesium and tyrosine kinases.


Tyrosine Kinases:  Can They Be Stuck “Off” Too?

Virtually everything I’ve read about tyrosine kinases mentions their role in cancer.  This is because it is known that protein kinases can become mutated, stuck in the “on” position, be constitutively expressed, and cause unregulated growth of the cell, which is a necessary step for the development of cancer.   Therefore, there is a tremendous amount of interest in researching kinase inhibitors as a treatment for cancer.     But nowhere have I seen any research, or even the suggestion of, what might happen when a protein kinase becomes stuck in the “off” position, or is simply functioning abnormally rather than “stuck on the ‘on’ position” all the time.    Given that some basic end results of protein kinase stimulation include cell growth, survival, migration, proliferation, glucose metabolism, angiogenesis, etc., it seems reasonable to assume that lack of stimulation, under-expression, or chronic or permanent inhibition of protein kinases/receptors would do the opposite (ie, slow down, inhibit, or stop normal cell growth, survival, migration, proliferation, glucose metabolism, angiogenesis, etc.).

The only clues we have so far as to what will happen in these scenarios is via research studies on the ADR’s of protein kinase inhibitors, such as I’ve presented here (see references below as well).    Arguments could be made that since these drugs are used in cancer patients, that there are other health issues contributing or causing these ADR’s.    Although this could be the case, it’s all we have right now to go on, and if the research is any indication, then I believe it’s showing legitimate adverse effects and symptoms.    But common sense says that chronic or permanent inhibition of these kinases in normal cells could be just as dangerous as chronic or permanent stimulation.    I would question if perhaps we’re seeing this more than we realize currently.    I would question whether some of these mechanisms might be involved in some of the common constellations of symptoms seen in Post Viral, Post Bacterial, Post Chemo, and Post FQ syndromes.    It’s well known that viruses, bacteria, and obviously, drugs can affect protein kinases and their actions.    Perhaps protein kinase lack of stimulation, under-expression, or chronic or permanent inhibition of protein kinases/receptors should be considered as yet another potential mechanism involved in so many of the “chronic mystery illnesses” (Chronic Fatigue Syndrome, Fibromyalgia, sero-negative autoimmune mystery illnesses).   On the other hand, since TK’s being “stuck on the ‘On’ position” is considered one potential mechanism as the cause of cancer, I find myself wondering why this might occur in the first place.   Could it be in response to an initial insult of tyrosine kinase inhibition, such as what might be caused by a virus, bacteria, or, in this case, a fluoroquinolone antibiotic?    In other words, if a TK is temporarily “bound up” or “inhibited” while on an FQ, perhaps a compensatory response would be to ramp up TK production, to the point it might become “stuck on the ‘On’ position” and constitutively expressed.   There are no statistics available on whether or not FQ’s contribute to cancer of any type.   But given the prevalence of FQ use in the population, their genotoxicity, and the long delayed adverse reactions, it wouldn’t surprise me if this were the case, although it would be pretty hard to prove (or disprove).

Kinase pathways are extensively and exquisitely interconnected and finely tuned.    I would imagine if one component was knocked out, it would create a huge “ripple” or “domino” effect.    I also suspect alternative pathways would attempt to compensate, perhaps more or less successfully, resulting in continued viability even if not optimally (ie, which may be why in my case, I so often feel like every cell of my body is physically dying, even as I continue to physically live).   Could the long, slow, delayed recoveries from any change in homeostasis I experience be due to under-expression or lack of appropriate tyrosine kinase stimulation?  Might be something to consider.


Can FQ’s Act as TKI’s?

Tyrosine kinases control a wide range of properties in proteins and are responsible for the activation of many proteins by signal transduction cascades.   Depending on which or how many of these kinases are being inhibited by the drugs targeting them, a variety of adverse effects can occur.  These drugs have turned some cancers, such as chronic myeloid leukemia, from a progressive fatal disease with a poor prognosis to a chronic condition similar to diabetes or hypertension.   So they are obviously life-saving for certain circumstances.   However, they also have an adverse effect profile, which includes some familiar sounding symptoms such as muscle cramps, musculoskeletal pain, joint pain, fatigue, arthralgia, myalgia, pharyngolaryngeal pain, dizziness, insomnia, depression, rash or other skin problems, abdominal pain, cardiac toxicity, headache, and more in addition to potential thyroid problems.   So far, the TKI’s are only being used for cancer patients, although their use is being explored for other conditions.   If it’s a choice between dying of cancer, or taking a TKI, most people would probably try the TKI.   I don’t know if the commonly prescribed FQ’s have the capability of acting like a TKI in addition to their function as chemotherapeutic TOPO inhibitors (although there is the suggestion of it; see below).   But if they do, it’s yet another reason that I certainly wouldn’t want to use them as a broad based antibiotic for simple, presumed, or suspected infections.

A search on “tyrosine kinase inhibitor” + “fluoroquinolone” brings up some hits, most notably, a patent application for  “4-fluoroquinolone derivatives and their use as kinase inhibitors”.   In addition to treating various cancers, they are being recommended for “inflammatory diseases that may be treated include, but are not limited to, atherosclerosis, rheumatoid arthritis (RA), insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, Chron’s disease, autoimmune nephritis, primary biliary cirrhosis, psoriasis, acute pancreatitis, allograph rejection, allergic inflammation, contact dermatitis and delayed hypersensitivity reactions, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, and cognition defects induced by neuronal inflammation.”    Hmmm . . . there’s a lot on this list that FQ’s are already contraindicated for, such as all the autoimmune conditions, diabetes, and osteoarthritis * .    In fact, this list kind of looks like the adverse effects list of FQ victims in general.   And at this point in time, I certainly couldn’t recommend taking an FQ to resolve “cognition defects” or “delayed hypersensitivity reactions” either.


*  See “Musculoskeletal Complications of Fluoroquinolones“, Page 136, Table 3, for potential risk factors for FQ usage.   See 2011 FDA Safety Warning stating that “FQ’s have neuromuscular blocking activity” for Myasthenia Gravis warnings.  Scroll through References for FQ-induced CNS symptoms including cognition defects, or see References NMDA GABA ACh for NMDA/GABA implicated FQ-induced CNS effects.  See “2- and 4- Quinolones” for background on quinolones. 

See the following for an introduction to Magnesium and Tyrosine Kinases:
Biochemistry of Magnesium
Divalent Cation Metabolism: Magnesium
Protein Tyrosine Kinase Structure and Function
Intracellular magnesium and insulin resistance
Inhibitory effect of fluoride on insulin receptor autophosphorylation and tyrosine kinase activity
Effect of cations on the tyrosine kinase activity of the insulin receptor: inhibition by fluoride is magnesium dependent
Separate effects of Mg2+, MgATP, and ATP4- on the kinetic mechanism for insulin receptor tyrosine kinase
Role of divalent metals in the activation and regulation of insulin receptor tyrosine kinase
The EGFR tyrosine kinase inhibitor tyrphostin AG-1478 causes hypomagnesemia and cardiac dysfunction
Dietary iodine affects epidermal growth factor levels in mouse thyroid and submaxillary glands
Fluoroquinolones cause changes in extracellular matrix, signalling proteins, metalloproteinases and caspase-3 in cultured human tendon cells
The Discoidin Domain Receptor Tyrosine Kinases Are Activated By Collagen
Ciprofloxacin-mediated inhibition of tenocyte migration and down-regulation of focal adhesion kinase phosphorylation  (Focal Adhesion Kinase also known as Protein Tyrosine Kinase 2).
Molecular mechanism of fluoroquinolones modulation on corneal fibroblast motility
Origin and evolution of the Trk family of neurotrophic receptors
Expression profile of receptor-type protein tyrosine kinase genes in the human thyroid
Thyroid Dysfunction From Antineoplastic Agents   FQ’s are anti-neoplastic (chemotherapeutic) agents, so perhaps it’s no surprise they may affect the thyroid so readily.
Metal Complexes of Quinolone Antibiotics and Their Applications: An Update
DNA cleavage and opening reactions of human topoisomerase IIα are regulated via Mg2þ- mediated dynamic bending of gate-DNA
Extracellular signal-regulated kinase activates topoisomerase IIalpha through a mechanism independent of phosphorylation  (Interesting:  TK’s themselves regulating human TOPO’s).
Endogenous expression of the sodium iodide symporter mediates uptake of iodide in murine models of colorectal carcinoma 
Molecular mechanism of fluoroquinolones modulation on corneal fibroblast motility
Discovery of a novel series of 4-quinolone JNK inhibitors   From Non-Antibiotic effects of fluoroquinolones in mammalian cells:    “Some quinolone-derived drugs bound strongly to the ATP binding pocket of JNK1”.    From Wiki “JNK1”:  “Activation occurs through a dual phosphorylation of threonine (Thr) and tyrosine (Tyr) residues . . . and JNK can be inactivated by Ser/Thr and Tyr protein phosphatases “
The DNA cleavage reaction of topoisomerase II: wolf in sheep’s clothing.   “All topoisomerases utilize active site tyrosyl residues to mediate DNA cleavage and ligation.”


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