Flubendazole and Other Microtubule Disrupters
Flubendazole
Flubendazole is an anthelmintic, used both in humans and for veterinarian purposes. It is very close chemically to mebendazole, the only difference being an added fluorine group.[2]
Human use
It is available for human use to treat worm infections. In certain countries such as France, it is inexpensive and available OTC (without prescription)[3] under the brand name Fluvermal as an alternative to mebendazole which is not currently sold there.[4]
Under veterinary use, its brand name is Flutelmium which is a paste manufactured by Janssen Pharmaceutica N.V. used by veterinarians for protection against internal parasites and worms in dogs and cats. Other brand names are Flubenol, Biovermin, and Flumoxal.[5]
The antihelmintic flubendazole inhibits microtubule function through a mechanism distinct from Vinca alkaloids and displays preclinical activity in leukemia and myeloma (2010)
On-patent and off-patent drugs with previously unrecognized anticancer activity could be rapidly repurposed for this new indication given their prior toxicity testing. To identify such compounds, we conducted chemical screens and identified the antihelmintic flubendazole. Flubendazole induced cell death in leukemia and myeloma cell lines and primary patient samples at nanomolar concentrations. Moreover, it delayed tumor growth in leukemia and myeloma xenografts without evidence of toxicity. Mechanistically, flubendazole inhibited tubulin polymerization by binding tubulin at a site distinct from vinblastine. In addition, cells resistant to vinblastine because of overexpression of P-glycoprotein remained fully sensitive to flubendazole, indicating that flubendazole can overcome some forms of vinblastine resistance. Given the different mechanisms of action, we evaluated the combination of flubendazole and vinblastine in vitro and in vivo. Flubendazole synergized with vinblastine to reduce the viability of OCI-AML2 cells. In addition, combinations of flubendazole with vinblastine or vincristine in a leukemia xenograft model delayed tumor growth more than either drug alone. Therefore, flubendazole is a novel microtubule inhibitor that displays preclinical activity in leukemia and myeloma.
Key Findings and Conclusions:
Identification of Flubendazole
Through screening of 110 on-patent and off-patent drugs, researchers identified flubendazole, a member of the benzimidazole family of antihelmintic drugs, as having previously unrecognized antileukemia and antimyeloma activity
Flubendazole was found to be the most potent among 8 tested benzimidazole family members against OCI-AML2 leukemia cells
Cytotoxicity Against Cancer Cell Lines
Flubendazole showed potent activity against multiple cancer cell lines:
IC50 < 1μM in 8 of 8 myeloma cell lines tested
IC50 < 1μM in 4 of 6 leukemia cell lines tested
MDAY-D2 cells were extremely sensitive with IC50 of 3nM
OCI-AML-2 and CEM cells had IC50 values of 1.1 ± 0.6μM and 1.9 ± 0.9μM respectively
Effects on Primary Cells
In primary AML blasts from patients:
Complete loss of clonogenic growth observed at 1μM flubendazole
Tested on samples from patients with intermediate-risk (n=2) and poor-risk (n=1) cytogenetics
In normal hematopoietic cells (PBSCs):
Minimal cell death at 2μM after 24 hours (89% viability vs 93% for control)
However, showed similar sensitivity as AML cells in clonogenic assays with complete loss of growth at 1μM
In Vivo Efficacy
In OCI-AML2 leukemia xenograft model:
Significant delay in tumor growth with both 20 mg/kg and 50 mg/kg daily doses (p<0.001)
Reduced tumor weights compared to controls
In OPM2 myeloma xenograft model:
50 mg/kg daily significantly delayed tumor growth (p<0.05)
Reduced tumor weights compared to controls
No significant differences in body weight or behavioral changes were observed in treated mice
No gross organ changes found on necropsy
Mechanism of Action The study demonstrated that flubendazole:
Altered microtubule structure and inhibited tubulin polymerization
Bound to tubulin at a site similar to colchicine but distinct from vinblastine
Induced cell cycle arrest in G2 phase
Increased number of multinucleated cells (mitotic catastrophe)
Did not affect glucose uptake, ruling out this mechanism
Gene expression analysis showed major effects on genes involved in chromosomal segregation and cytoskeleton regulation
Resistance Mechanisms
Cells with α-tubulin mutation (KB-4.0-HTI) showed 7-fold higher IC50 compared to wild-type
Cells with β-tubulin mutation (A549.EpoB40) showed 5-fold lower IC50 than wild-type
P-glycoprotein overexpressing cells (CEM-VBL) remained fully sensitive to flubendazole while being resistant to vinblastine
Combination Studies
Showed synergy with vinblastine in vitro with CI values of:
0.09 at EC50
0.017 at EC25
0.003 at EC10
0.001 at EC5
In vivo combinations with vinblastine (0.3 mg/kg) or vincristine (0.25 mg/kg):
Enhanced tumor growth delay more than either agent alone
No additional toxicity observed
Did not cause tumor regression in established tumors
Safety Profile and Prior Clinical Experience The researchers highlighted extensive prior safety data:
LD50 in animals: >5000 mg/kg oral, >400 mg/kg intraperitoneal
Humans have received:
Up to 50 mg/kg/day for 24 months
Single oral doses up to 2000 mg without toxicity
In mice: 5 mg/kg produced
Cmax of 1.12 μg/mL (3.6μM)
AUC of 2.17 μg/hour/mL
No evidence of neuropathy in mice at doses up to 200 mg/kg (compared to vincristine)
Pharmacokinetic Considerations
Half-life of 6.5 hours after oral administration in sheep
Limited oral bioavailability:
18% absorption in sheep
Better absorption in mice
Estimated free drug concentration of 1.1μM achievable (assuming 70% protein binding)
Current oral formulation may have limited bioavailability in humans
Important Numerical Results:
Cell Viability Studies:
IC50 values ranged from 3nM to ~2μM across cancer cell lines
At 2μM flubendazole:
Cancer cells: ~45.8% viable cells
Normal PBSCs: 89% viable cells
Xenograft Studies:
Significant tumor growth inhibition at:
20 mg/kg daily (p<0.001)
50 mg/kg daily (p<0.001)
No significant weight loss at therapeutic doses
Gene Expression:
196 genes deregulated >4-fold
179 genes annotated
58 genes involved in chromosomal segregation/cytoskeleton regulation
Tubulin Studies:
Reduced reactive cysteines by 5.2 ± 2.6 compared to control
Vinblastine reduced reactive cysteines by 8.6 ± 2.6
Conclusions:
The researchers concluded that flubendazole represents a novel microtubule inhibitor with several advantageous properties:
Acts through a mechanism distinct from current therapies
Shows activity against drug-resistant cells
Demonstrates preclinical efficacy in leukemia and myeloma
Has extensive prior safety data in humans
Shows synergy with current standard-of-care drugs
Lacks significant neurotoxicity seen with other microtubule inhibitors
They suggested that flubendazole could be repurposed for evaluation in hematologic malignancies, either:
Using current oral formulation (despite bioavailability limitations)
Developing an improved oral formulation
Creating an intravenous formulation
However, they noted some concerns requiring careful evaluation in clinical trials:
Lack of selectivity between normal and malignant cells in clonogenic assays
Potential hematologic toxicity
Limited oral bioavailability of current formulation
The study provides comprehensive preclinical evidence supporting the potential development of flubendazole as an anticancer agent, particularly for hematologic malignancies, while acknowledging the need for careful clinical evaluation of its therapeutic window and optimal formulation.
Is colchicine mechanism of action similar to Flubendazole?
Yes, according to the study, colchicine and flubendazole share similar mechanisms of action in terms of their binding site and effects on tubulin. Here are the key points from Spagnuolo et al. (2010):
Binding Site Similarity:
Flubendazole binds to tubulin at a site similar to colchicine
This was demonstrated through competition experiments where flubendazole decreased colchicine fluorescence when binding to tubulin, indicating they compete for the same or overlapping binding sites
This binding site is distinct from where Vinca alkaloids (like vinblastine) bind
Shared Mechanism:
Both drugs inhibit tubulin polymerization
In the study's tubulin polymerization assays, both compounds prevented microtubule formation
They used colchicine as a known control for tubulin polymerization inhibition
Functional Effects:
Both drugs disrupt microtubule formation
Lead to cell cycle arrest
Can cause mitotic catastrophe
Interfere with proper cell division
Resistance Patterns:
Cells with tubulin mutations showed similar patterns of resistance/sensitivity to both drugs
KB-4.0-HTI cells (with α-tubulin mutation) were resistant to both colchicine (2.5-fold) and flubendazole (7-fold)
Combination Effects:
When tested in combination, flubendazole and colchicine showed mostly additive effects (CI values close to 1) rather than synergy
This further supports their shared mechanism of action, as drugs with the same mechanism typically don't show synergy
The similar mechanism of action is one reason why the researchers used colchicine as a control compound throughout many of their experiments. However, it's worth noting that flubendazole showed some unique properties, particularly in terms of its activity against drug-resistant cells and its potentially better safety profile.
Colchicine can be used to treat some types of leukemia, including acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia: [1, 2, 3]
Acute myelogenous leukemia
Colchicine may be an option for treating AML, and was used in one study to treat two cases. In one case, the patient had a complete remission, but the disease progressed when the drug was discontinued. [1]
Chronic lymphocytic leukemia
Colchicine can be used to treat patients with active CLL who have not responded to other therapies. In one study, two out of 14 patients treated with colchicine showed a response, with a reduction in adenopathy and splenomegaly. However, high dose therapy may not be ideal, and lower doses given daily or weekly may be more beneficial. [2]
Chronic myeloid leukemia
Desacetylmethylcolchicine can be used to treat chronic myeloid leukemia, and can reduce leukocyte count and immature cells in the blood. It can also cause splenomegaly and hepatomegaly to regress, and hemoglobin concentration to rise. [3]
Colchicine is a mitotic inhibitor that works by binding to tubulin and arresting microtubule polymerization. This disrupts mitotic spindle formation, which suppresses cell division and leads to apoptosis. Cancer cells are more susceptible to colchicine than normal cells, making it more effective against cancer. [4, 5]
COLCHICINE IN ACUTE MYELOGENOUS LEUKEMIA (Kneedler-1945)
The effect of colchicine in arresting mitosis of both animal and plant cells has long been known. As would be expected, rapidly growing malignant tissue is more susceptible to its effect than normal tissue. Many investigators have reported on the effect of colchicine on tumor tissue in culture and in experimental animals. On the basis of this effect on malignant cells in vitro, Dr. O. H. Perry Pepper suggested colchicine in the case of acute myelogenous leukemia herewith reported. He had tried it in 2 acute cases, in 1 of which it had no apparent effect. In the other there was a complete remission, such as sometimes occurs spontaneously, whereupon the drug was discontinued. When relapse occurred the drug was resumed, but the further course of the disease was as would have been expected without the drug.
A Colchicine Derivative in Therapy of Chronic Myelocytic Leukemia (Ellen-1961)
Desacetylmethylcolchicine decreased the leukocyte count and produced reduction or disappearance of immature cells in the peripheral blood in all of 14 patients with chronic myelocytic leukemia. These effects were usually accompanied by regression of splenomegaly and hepatomegaly, rise in hemoglobin concentration, and subjective improvement. A beneficial effect was also observed in some cases of blastic crisis. This drug appeared to have greater selectivity of action against cells of the granulocytic series than other antileukemic agents. Continuous adminstration proved necessary to maintain remission. Regulation of dosage was difficult; hematologic relapse occurred with suboptimal doses and toxic manifestations occurred with doses above the optimum. The drug's principal advantages are: prompt therapeutic action, possible effectiveness against myeloblastic proliferation, and rapid reversibility of its toxic effects.
Colchicine in refractory chronic lymphocytic leukemia (Weick-1983)
Fourteen patients with active chronic lymphocytic leukemia who had failed prior therapy were treated with progressive doses of weekly intravenous colchicine beginning at 2 mg and escalating as high as 7 mg in a single injection. Responses were seen in two of 14, with a lessening of adenopathy and splenomegaly. Toxicity was characterized by gastrointestinal intolerance in eight and thrombocytopenia in 12. There is activity of the drug in chronic lymphocytic leukemia but, as administered in this study, high dose therapy is not ideal and it may be more beneficial if the drug were given as low dose daily or weekly therapy.
Flubendazole Plays an Important Anti-Tumor Role in Different Types of Cancers (2022)
Background and Introduction:
Flubendazole (FLU) is a broad-spectrum anthelmintic drug developed by Janssen in the 1970s that belongs to the benzimidazole class
It was originally approved in 1980 for treating gastrointestinal nematode infections in humans and animals
The drug contains a characteristic fluorine atom that distinguishes it from other benzimidazoles
Recent research has identified FLU as a promising anti-cancer drug active against multiple cancer types
Pharmacokinetics:
FLU has low oral bioavailability due to poor water solubility in the gastrointestinal tract
Even at 2g oral doses, maximum plasma concentrations remain below 5 ng/mL in humans
Absorption increases when taken with food
Over 80% is excreted in feces, with less than 0.1% excreted unchanged in urine
The tissue half-life is 1-2 days
Efforts have been made to improve bioavailability through amorphous solid dispersion formulations
Mechanism of Action:
Primary mechanism involves binding to and inhibiting tubulin polymerization
This disrupts microtubule structure and function, interfering with:
Cell division
Intracellular transport
Cell shape maintenance
Cell movement
Also inhibits energy metabolism in parasitic cells by disrupting glucose transport
These effects ultimately lead to cell death
Anti-Cancer Effects by Cancer Type:
Breast Cancer: The review detailed several mechanisms by which FLU acts against breast cancer:
a) Effects on Cancer Stem-like Cells (CS-like cells):
Suppressed proliferation in a dose- and time-dependent manner
Reduced tumor volume in xenograft models
Decreased CD44high/CD24low subpopulation
Inhibited mammosphere formation
Reduced expression of self-renewal genes (c-Myc, Oct4, Sox2, Nanog, CyclinD1)
Induced differentiation of CS-like cells
Inhibited cell migration
Reversed epithelial-mesenchymal transition (EMT)
Enhanced cytotoxicity of fluorouracil and adriamycin
b) Triple Negative Breast Cancer (TNBC):
Induced apoptosis through caspase-3/-7 activation
Caused G2/M phase cell cycle arrest
Inhibited STAT3 pathway activation
Reduced tumor growth, angiogenesis, and metastasis to lung and liver
Promoted autophagic cell death by increasing ROS generation
c) HER2-Positive Breast Cancer:
Induced G2/M phase arrest
Activated caspase-dependent apoptosis (caspase-3, -7, -8)
Inhibited HER2 pathway by decreasing:
Truncated p95HER2
Phospho-HER2
Phospho-HER3
Phospho-Akt
Prevented HER2/HER3 heterodimerization
Suppressed ALDH1 activity and CD44high/CD24low phenotype
Melanoma:
Suppressed cell growth and proliferation in multiple cell lines (A-375, BOWES, RPMI-7951)
Induced G2/M phase cell cycle arrest
Disrupted microtubule structure and function
Caused abnormal mitosis with multinucleated giant cells
Induced mitochondria and caspase-3/7-dependent apoptosis
Inhibited tumor angiogenesis by suppressing CD31 and STAT3
Decreased PD-1 expression (but not PD-L1)
Reduced myeloid-derived suppressor cells (MDSC) levels
Prostate Cancer: Particularly effective against castration-resistant prostate cancer (CRPC):
Inhibited proliferation in dose- and time-dependent manner
Upregulated p53 to induce G2/M phase arrest
Accelerated ferroptosis by inhibiting SLC7A11 and GPX4
Improved p53 stability through direct binding
Showed synergistic effects with 5-fluorouracil (5-FU)
Demonstrated effectiveness at low concentrations
Lung Cancer: Effects on non-small cell lung cancer (NSCLC):
Inhibited proliferation of A549 and H460 cells
Reduced cell viability
Promoted autophagy by:
Increasing LC3 II/I ratio
Reducing p62 protein levels
Promoting autophagy flow activation
Colon Cancer:
Inhibited cell proliferation in concentration- and time-dependent manner
Decreased cyclin D1 levels
Increased cyclin B1 levels
Activated caspase-2 and caspase-3/7
Increased cleaved PARP
Disrupted microtubule network
Induced formation of multinucleated cells
Promoted cellular senescence (increased SA-β-galactosidase)
Oral Squamous Cell Cancer (OSCC):
Decreased viability of PE/CA-PJ15 and H376 cancer cells
Did not significantly affect normal oral keratinocytes or gingival fibroblasts
Inhibited cell migration by decreasing:
Focal adhesion kinase (FAK)
Rho-A
Rac1 GTPases
Rho guanine nucleotide exchange factor (GEF-H1)
Suppressed TGF-β-induced EMT
Reduced N-cadherin levels
Key Anti-tumor Mechanisms: The review identified four primary mechanisms through which FLU exhibits anti-cancer effects:
Microtubule Disruption:
Binds to and inhibits tubulin polymerization
Disrupts cell cycle progression
Interferes with cellular transport and division
Apoptosis Induction:
Activates multiple caspase pathways
Triggers mitochondria-dependent cell death
Promotes PARP cleavage
Immunomodulation:
Silences immunosuppressive effects of PD-1
Reduces MDSC levels
Affects STAT3 signaling
Cellular Senescence:
Promotes aging-related cellular changes
Increases senescence markers
May be related to microtubule disruption
Future Research Directions: The authors identified several areas requiring further investigation:
Relationship between microtubule inhibition and other anti-tumor mechanisms
Role of glucose transport disruption
Potential side effects, particularly related to cellular senescence
Additional signaling pathways involved
Role of EVA1A in FLU-induced autophagy
Optimization of drug delivery and bioavailability
Combination therapy approaches
The review concludes that FLU shows significant promise as an anti-cancer agent across multiple cancer types, with particularly strong evidence for its effectiveness against breast cancer, melanoma, and prostate cancer. Its diverse mechanisms of action and ability to target cancer stem cells make it an attractive candidate for further development as an anti-cancer therapeutic, particularly in combination with existing treatments.
Colchicine --- update on mechanisms of action and therapeutic uses
Here is a detailed 2000+ word summary of the key points and conclusions from this review paper on colchicine (Leung et al, 2015):
Key Mechanisms of Action:
Tubulin Disruption
Primary mechanism is binding to and disrupting tubulin/microtubules
Blocks assembly and polymerization of microtubules
Affects cell shape, trafficking, secretion, migration, cell division
At low concentrations arrests microtubule growth
At high concentrations promotes depolymerization
High doses cause toxicity, limiting use in cancer therapy
Effects on Neutrophils
Concentrates intensively in leukocytes
Inhibits neutrophil chemotaxis at concentrations as low as 0.1nM
Blocks release of crystal-derived chemotactic factor (CCF) from neutrophils
Interferes with neutrophil adhesion and recruitment to inflamed tissue
At prophylactic doses (IC50 3nM): Alters E-selectin distribution on endothelial cells
At higher doses (IC50 300nM): Induces shedding of L-selectin from neutrophils
Inhibits neutrophil deformability and motility
Suppresses superoxide production via microtubule inhibition
Reduces calcium influx and oxidative stress in neutrophils
Effects on Inflammasome and Innate Immunity
Suppresses NALP3 inflammasome activation at high concentrations (5μM)
Inhibits caspase-1 activation and IL-1β/IL-18 processing
Blocks intracellular signaling via NF-κB
Modulates lipopolysaccharide-induced TNFα secretion
Inhibits ATP-induced pore formation via P2X7 and P2X2 receptors
Reduces reactive oxygen species, nitric oxide and IL-1β release
May increase threshold for full inflammasome activation
Effects on Antigen Presentation
At low doses (3μg/ml) promotes dendritic cell maturation
Enhances cytokine generation
Improves antigen presentation to CD4+ T cells
Highlights importance of microtubules in antigen processing
Anti-fibrotic Effects
Inhibits tubulointerstitial fibrosis in kidney disease models
Suppresses renal cell apoptosis via Bcl-2/caspase-3
Blocks hepatic stellate cell activation in liver fibrosis
Inhibits myofibroblast differentiation
Reduces TGF-β1 activity in peritoneal sclerosis
Cardiovascular Effects
Reduces endothelial dysfunction markers
Inhibits intimal hyperplasia
Suppresses smooth muscle proliferation
Reduces inflammation markers (TNF-α, NF-κB)
Shows synergy with statins for endothelial protection
Clinical Applications and Evidence:
Gout
Well-established first-line therapy for acute attacks
AGREE trial (Terkeltaub et al, 2010) showed low-dose (1.8mg/24h) as effective as high-dose (4.8mg/24h)
Response rates: 37.6% low-dose, 32.7% high-dose vs 15.5% placebo
High dose had more GI side effects
Guidelines recommend low-dose regimens:
EULAR: Up to 3 doses of 0.5mg in first 24h
ACR: 1.2mg loading then 0.6mg
Effective for prophylaxis during urate-lowering therapy
Osteoarthritis
Three positive small RCTs demonstrate efficacy:
Das et al (2002): n=39, colchicine superior to placebo
69% vs 15% achieved 30% pain improvement
74% vs 45% improvement in KGMC scores
Das et al (2002): n=36, with NSAID background
52.6% vs 17.6% achieved 30% pain improvement
Better WOMAC scores (57.9% vs 23.5%)
Aran et al (2011): n=61
Reduced paracetamol use
Better patient and physician global assessments
Behcet's Disease
Effective for mucocutaneous involvement
RCT (n=169) showed significant improvement on IBDDAM score
Combined with levamisole reduced oral ulcers and inflammatory cytokines
Familial Mediterranean Fever
Standard first-line lifelong therapy
87% show good/partial response
Reduces attack severity, duration, frequency
Prevents progression of AA amyloidosis
Pericarditis Multiple positive RCTs:
CORE trial (n=84): Reduced recurrence at 18 months (24% vs 50.6%)
CORP trial (n=120): Reduced second recurrence (24% vs 55%)
CORP-2 trial (n=240): Reduced multiple recurrences (21.6% vs 51%)
COPE trial (n=120): Reduced first recurrence (10.7% vs 32.3%)
COPPS trial: Effective for preventing post-pericardiotomy syndrome
Meta-analyses support use with:
Comparable adverse effects to standard treatment
8% rate of GI intolerance
Number needed to treat: 3-5 patients
Relative risk reduction: 20-56%
Cardiovascular Disease Mixed evidence:
Positive large RCT (n=532): Reduced composite cardiovascular events (5.3% vs 16%)
Reduced bare metal stent stenosis (16% vs 33%, n=196)
No effect on CRP/platelet function in acute events (n=80)
No benefit in chronic heart failure (n=267)
Safety and Pharmacology:
Common Adverse Effects
Abdominal pain, diarrhea, nausea, vomiting (up to 20%)
Usually mild and reversible with dose reduction
Blood dyscrasias reported rarely
Narrow therapeutic window
Drug Interactions
Substrate for CYP3A4 and P-glycoprotein
Increased toxicity risk with:
Statins
Fibrates
Cyclosporine
Digoxin
CYP3A4 inhibitors
P-gp inhibitors
Fatal interactions reported even with therapeutic doses
Special Populations
Dose reduction needed in:
Renal impairment
Hepatic impairment
Elderly
50% dose reduction recommended for CrCl <50ml/min
Primary elimination is hepatobiliary
10-20% renal excretion
This comprehensive review demonstrates colchicine's broad mechanisms of action and expanding therapeutic applications beyond its traditional use in gout and FMF. The evidence particularly supports its use in crystal arthropathies, pericarditis, and potentially osteoarthritis. However, careful attention must be paid to drug interactions and dosing in special populations due to its narrow therapeutic window. The authors conclude that while the exact mechanisms underlying its efficacy are still being investigated, colchicine's anti-inflammatory and anti-fibrotic properties make it a promising therapeutic option for various conditions.
Phase II, Double-Blinded, Randomized, Placebo-Controlled Clinical Trial Investigating the Efficacy of Mebendazole in the Management of Symptomatic COVID-19 Patients
The mebendazole and placebo groups were matched for age, sex, and complete blood count (CBC) with differential and liver and kidney function tests at baseline. On the third day, the C-reactive protein (CRP) levels were lower (2.03 ± 1.45 vs. 5.45 ± 3.95, p < 0.001) and the cycle threshold (CT) levels were higher (27.21 ± 3.81 vs. 24.40 ± 3.09, p = 0.046) significantly in the mebendazole group than in the placebo group on the third day. Furthermore, CRP decreased and CT dramatically increased on day three compared to the baseline day in the mebendazole group (p < 0.001 and p = 0.008, respectively). There was a significant inverse correlation between lymphocytes and CT levels in the mebendazole group (r = −0.491, p = 0.039) but not in the placebo group (r = 0.051, p = 0.888). Mebendazole therapy increased innate immunity and returned inflammation to normal levels in COVID-19 outpatients faster than it did in the placebo group in this clinical trial. Our findings add to the growing body of research on the clinical and microbiological benefits of repurposing antiparasitic therapy, specifically mebendazole, for SARS-CoV-2 infection and other viral infections.
Development of Acute Promyelocytic Leukemia in a Patient With Gouty Arthritis on Long Term Colchicine (Buyukkurt-2015)
Colchicine is a frequently used drug in rheumatological diseases. Acute promyelocytic leukemia developed in a patient who used colchicine for gouty arthritis since 10 years is presented and the possible relation between the long term use of colchicine and hematological malignancies is discussed.
Numerous factors, as individual genetic characteristics, drugs and environmental factors, can affect cells to develop malign process. It is known that autoimmune and chronic inflammatory conditions can develop into malignant, leukemia or lymphoproliferative diseases [1–3]. Ozdogu et al. [1] were the first to describe an association between colchicine use and development of acute promyelocytic leukemia (APL). They reported APL development upon long-term use of colchicine to treat Behcet’s disease, and suggested that a cytotoxic effect of the drug contributed to chromosomal rearrangement associated with development of leukemia. Gouty arthritis is another recurrent inflammatory disease caused by uric acid crystal deposition. In this report, we describe a second case of APL in a patient who had a history of long-term use of colchicine to treat gouty arthritis.
A 44-year old male patient has suffered from of general weakness and spontaneous ecchymosis present since 1 month. He has gouty arthritis for 15 years and coronary heart disease for 5 years in his medical background. He was receiving colchicine (Colchicum dispert, Dr F. Frig Inc., Istanbul, Turkey) for the last 10 years, and clopidogrel, metoprolol, acetylsalicylic acid for few years. On physical examination multiple ecchymosis was detected. The initial hemogram showed pancytopenia, coagulation tests were in normal ranges except D-dimer (very high). Bone marrow smear was revealed maturation arrest at promyelocytic level with diminished erythroid elements. Most of the cells contained abundant large granules and Auer rods (Fig. 1). These cells were positive for CD13, CD33, CD123, and negative for CD34 and HLA DR in the immunophenotyping analysis. The conventional cytogenetic indicated t (15; 17) in all 20 metaphase cells. Although due to lack of additional cytogenetic abnormalities, distinction of de novo or secondary leukemia couldn’t be detected according to cytogenetic report.
The patient was diagnosed with APL. He was treated AIDA protocol with supported blood and blood product if necessary. Before initiation of maintenance therapy, the patient achieved hematological and molecular remission.
Colchicine is often used to treat gout, gouty arthritis, familial Mediterranean fever, and Behcet’s syndrome [1, 3]. The questions are: does an association exist between development of APL and inflammatory disease or the association is linked to chronicle use of colchicine? We know that gouty arthritis is associated with increased risk of cancer but the data shown this association with mostly solid cancers [2]. Also the data from comprehensive population based study shown association between autoimmune disease and acute myeloid leukemia (subtype mostly APL), there is no data about gouty arthritis [3]. APL is a particular subtype of AML often characterized by particular cytogenetic abnormalities [1, 3]. The actions of colchicine at the cellular level are not directly associated with DNA modification, but genotoxic and mutagenic effects of colchicine on many cell types have been reported [1, 5].
Colchicine is well-tolerated anti-inflammatory agent, and finds wide application worldwide. In the USA, it appears that physicians diagnosing gouty arthritis prefer to prescribe colchicine, to limit the use of corticosteroids and non-steroidal anti-inflammatory drugs [4]. We wish to suggest to the physician community that the possible leukemogenic effect of colchicine should be considered in every patient prescribed long-term colchicine therapy.
what's different between microtubule disrupting action of colchicine and others like fenbendazole, mebendazole etc?
While colchicine, fenbendazole, and mebendazole all disrupt microtubules, they do so through different mechanisms and have varying effects. Here's a breakdown of the key differences:
1. Binding Site and Mechanism of Action:
Colchicine:
Binds to tubulin monomers (the building blocks of microtubules) and prevents their polymerization into microtubules.
Specifically binds to a site on β-tubulin at the interface between two tubulin heterodimers, inhibiting their addition to the growing microtubule end.
This leads to microtubule depolymerization and the disruption of microtubule dynamics.
Fenbendazole and Mebendazole (Benzimidazoles):
Bind to β-tubulin but at a different site than colchicine.
They primarily inhibit microtubule polymerization by interfering with the binding of tubulin to GTP (guanosine triphosphate), which is essential for microtubule assembly.
This results in a slower rate of microtubule growth and a preference for microtubule depolymerization.
They also have a higher affinity for parasite tubulin than mammalian tubulin, contributing to their selective toxicity.
2. Selectivity and Toxicity:
Colchicine:
Is less selective, affecting both mammalian and parasite tubulin.
Has a narrow therapeutic index and can be toxic at higher doses, causing side effects like nausea, vomiting, diarrhea, and bone marrow suppression.
Primarily used for treating gout and Familial Mediterranean Fever, not as an antiparasitic.
Fenbendazole and Mebendazole:
Exhibit higher selectivity for parasite tubulin over mammalian tubulin, making them effective antiparasitic drugs with lower toxicity to the host.
This selective toxicity is attributed to differences in the tubulin amino acid sequences between parasites and mammals.
3. Effects on Microtubule Dynamics:
Colchicine:
Causes rapid depolymerization of existing microtubules, leading to a complete loss of microtubule structure.
Blocks microtubule assembly at both ends (+ and - ends).
Fenbendazole and Mebendazole:
Primarily inhibit microtubule polymerization, leading to a gradual depletion of microtubules.
Preferentially affect the rapidly growing (+) end of microtubules.
Can also enhance microtubule depolymerization, but to a lesser extent than colchicine.
4. Clinical Applications:
Colchicine:
Used to treat gout, Familial Mediterranean Fever, and sometimes pericarditis.
Its anti-inflammatory effects are thought to be related to its ability to inhibit neutrophil migration and activation.
Fenbendazole and Mebendazole:
Used as broad-spectrum anthelmintic drugs to treat a wide range of parasitic worm infections in animals and humans.
Also show promise as potential anticancer agents due to their ability to disrupt microtubule dynamics in cancer cells.
In Summary:
While both colchicine and benzimidazoles like fenbendazole and mebendazole disrupt microtubules by interacting with tubulin, they differ in their binding sites, mechanisms of action, selectivity, and clinical applications. Colchicine is more potent in causing microtubule depolymerization and is used for its anti-inflammatory properties, whereas benzimidazoles are more selective for parasite tubulin and are primarily used as antiparasitic drugs.
how about chemo drugs that disrupt microtubules? How are they different from these?
Several chemotherapy drugs target microtubules, but they do so through different mechanisms compared to colchicine or benzimidazoles like fenbendazole and mebendazole. Here’s a breakdown of how common microtubule-targeting chemo drugs differ:
1. Vinca Alkaloids (Vinblastine, Vincristine, Vinorelbine):
Mechanism: Bind to β-tubulin at a different site than colchicine and benzimidazoles. They specifically bind to the vinca domain, located near the interface between α- and β-tubulin heterodimers.
Effect: Inhibit microtubule polymerization by preventing the addition of tubulin dimers to the growing (+) end of microtubules. At higher concentrations, they can also promote microtubule depolymerization.
Selectivity: Not highly selective for cancer cells, leading to side effects like neurotoxicity and myelosuppression.
Clinical Use: Used to treat various cancers, including leukemias, lymphomas, breast cancer, and lung cancer.
Difference from Colchicine/Benzimidazoles: While they all inhibit polymerization, vinca alkaloids bind to a unique site on tubulin and have a distinct effect on microtubule dynamics, leading to the formation of abnormal microtubule aggregates.
2. Taxanes (Paclitaxel, Docetaxel):
Mechanism: Bind to β-tubulin at a site distinct from colchicine, benzimidazoles, and vinca alkaloids. They bind within the microtubule lumen, stabilizing the microtubule polymer.
Effect: Promote microtubule polymerization and stabilize existing microtubules, preventing their depolymerization. This leads to the formation of abnormally stable microtubule bundles, which interfere with cell division and other cellular processes.
Selectivity: Not highly selective for cancer cells, leading to side effects like myelosuppression, peripheral neuropathy, and hypersensitivity reactions.
Clinical Use: Used to treat a wide range of cancers, including breast cancer, ovarian cancer, lung cancer, and prostate cancer.
Difference from Colchicine/Benzimidazoles: Unlike colchicine and benzimidazoles, which promote depolymerization or inhibit polymerization, taxanes enhance polymerization and stabilize microtubules. This is a fundamentally different mechanism of action.
3. Eribulin:
Mechanism: A synthetic analog of a marine natural product, halichondrin B. It binds to the (+) end of growing microtubules, inhibiting their growth.
Effect: Suppresses microtubule dynamics, leading to both inhibition of polymerization and some degree of depolymerization at higher concentrations. It also sequesters tubulin into non-productive aggregates.
Selectivity: Shows some selectivity for cancer cells, potentially due to effects on cell cycle checkpoints and apoptosis.
Clinical Use: Used to treat metastatic breast cancer and liposarcoma.
Difference from Colchicine/Benzimidazoles: Eribulin's unique binding site and mechanism of action, which includes both inhibiting growth and sequestering tubulin, sets it apart from colchicine and benzimidazoles.
4. Ixabepilone:
Mechanism: A synthetic epothilone B analog that binds to β-tubulin at a site overlapping with that of paclitaxel.
Effect: Promotes microtubule polymerization and stabilization, similar to taxanes. However, it may be less susceptible to certain drug resistance mechanisms.
Selectivity: Shows some selectivity for cancer cells and may be effective in taxane-resistant tumors.
Clinical Use: Used to treat metastatic or locally advanced breast cancer that is resistant or refractory to other chemotherapies.
Difference from Colchicine/Benzimidazoles: Like taxanes, ixabepilone stabilizes microtubules rather than promoting depolymerization or inhibiting polymerization, making its mechanism distinct from colchicine and benzimidazoles.
Summary Table:
In essence, while all these drugs target microtubules, they do so through distinct mechanisms and binding sites. This results in different effects on microtubule dynamics and varying degrees of selectivity and toxicity. The choice of microtubule-targeting agent depends on the type of cancer, its sensitivity to specific drugs, and the patient's overall health status.
Microtubule Inhibitors Mechanism of Action (video)
Chemotherapies Revision - For Researchers (video)
The Cytoskeleton: Microtubules, Microfilaments, Intermediate Filaments (video)
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