Après les médicaments anthelminthiques (vermifuges), poursuivons l’exploration du « Janus » biologique décrit dans le chapitre 14 de mon livre : les produits antifongiques (naturels ou synthétiques) ont également des propriétés anticancéreuses. Et inversement.
C’est presque une constante. Pourquoi ?
On vous répondra sans doute que ces cellules sont toutes des eucaryotes. C’est donc normal. Cela revient à dire qu’une brouette et un avion à réaction sont de même nature (des « moyens de transport ») et qu’ils possèdent la même structure. Ou encore comparer un humain à un poisson. Ou à une plante… On comprend bien que ce n’est pas si simple.
Définition : « un eucaryote est un organisme vivant, unicellulaire ou pluricellulaire, dont les cellules possèdent un vrai noyau séparé du cytoplasme par une membrane« .
Si votre crème contre les mycoses se mettait à détruire les cellules de votre peau en plus de celles du champignon, cela ferait jaser. Explication technique : les imidazoles ciblent -entre autres- l’ergostérol qui compose la membrane des cellules fongiques alors que les cellules humaines utilisent du cholestérol.
Ces médicaments agissent donc sur des cellules fongiques, des cellules cancéreuses mais pas (ou moins) sur des cellules humaines saines. On parle alors de spécificité. Un concept clé.
Mes amis thaïlandais utilisent une expression qui résume bien la problématique : « same same but different« . 😉
Concernant le repositionnement de ces médicaments, l’angle que j’aime utiliser est celui des… brevets. Pourquoi ? Parce que la célèbre tirade du personnage de Gordon Gecko (film Wall Street, 1987).
Greed, for lack of a better word, is good. Greed is right, greed works. Greed clarifies, cuts through and captures the essence of the evolutionary spirit. Greed in all of its forms. Greed for life, money, love, knowledge, has marked the upward surge of mankind.
Et ensuite parce que certains déposants sont prestigieux, voire incontestables.
Un exemple : Johns Hopkins qui est une célèbre université américaine et un centre anti-cancer reconnu, a déposé 2 brevets en 2016 et 2019 liant le mébendazole (oui, le vulgaire vermifuge créé dans les années 70 par Janssen, filiale de Johnson&Johnson) à des applications anticancéreuses.
Preuve 1 : https://patents.google.com/patent/US11110079B2/en
Preuve 2 : https://patents.google.com/patent/US11712435B2/en
Le judo mental s’impose ainsi naturellement : tous les affidés de Big Pharma, ses zélotes et autres oncologues d’opérette… aucun ne peut se déclarer plus compétent que les chercheurs de Johns Hopkins.
« Faites confiance à la science« , disaient-ils. N’est-ce pas ?
En d’autres termes : si depuis un demi siècle (dans le cas des benzimidazoles carbamates !) des institutions importantes, un peu partout dans le monde, déposent des brevets, alors il n’y a pas de fumée sans feu, comme disaient nos grands-pères.
Revenons à notre sujet : les médicaments antifongiques. La famille la plus connue est celle des azoles. Elle se divise en 2 groupes : les imidazolés et les triazolés.
Des noms ? Fluconazole, clotrimazole, itraconazole, métronidazole, miconazole, kétoconazole, oxiconazole, suconazole, butoconazole, etc.
On les utilise (crème, voie orale, injection) contre les mycoses, les candidoses et autres infections fongiques. Certains possèdent également des propriétés antibactériennes.
Je vous propose le même exercice que pour les benzimidazoles carbamates : une recherche en lien avec le cancer dans la base de données Google Patents.
Liste non exhaustive. On trouve en effet d’autres brevets mais qui ajoutent des molécules autour d’un noyau imidazole/triazole (pour de réelles propriétés supplémentaires ou simplement pour rendre la préparation « originale » et donc plus facilement brevetable). Mais leurs formules chimiques s’éloignent des antifongiques classiques.
Et le dernier est récent : 2024.
Quand un hôpital en Chine spécialisé dans le cancer nous parle du clotrimazole pour le traitement du cancer des ovaires… nous devrions peut-être ravaler notre fierté et tendre l’oreille.
https://patents.google.com/patent/CN118021804A/en
cdubuit@onconautes.com
1987, Etats-Unis (Merck and Co)
5-Amino or substituted amino 1,2,3,-triazoles useful as antiproliferative agent
https://patents.google.com/patent/US4847257A/en
1993, Etats-Unis (Harvard University)
Cancer treatments (Preferred imidazoles are clotrimazole, miconazole and econazole)
https://patents.google.com/patent/US5633274A/en
1993, Etats-Unis (US Department of Health and Human Services)
1,2,3-triazole and imidazole compounds and their antitumor use
https://patents.google.com/patent/WO1993025536A1/en
1995, Etats-Unis (Procter&Gamble)
Pharmaceutical composition for inhibiting the growth of cancers
https://patents.google.com/patent/US5770616A/en
1996, Etats-Unis (Procter&Gamble)
Use of fluconazole for inhibiting the growth of cancers
https://patents.google.com/patent/WO1997005873A2/en
1995, Etats-Unis (Boston Childrens Hospital, Harvard University)
Method for treating epithelial precancerous lesions with topical imidazoles
https://patents.google.com/patent/US5556871A/en
1996, Etats-Unis (Procter&Gamble)
Use of 1h-1,2,4-triazole derivatives for inhibiting the growth of cancers
https://patents.google.com/patent/WO1997005872A2/en
1996, Etats-Unis (Merck and Co Inc.)
Substituted imidazoles having anti-cancer and cytokine inhibitory activity
https://patents.google.com/patent/WO1997012876A1/en
1996, Etats-Unis (Merck and Co Inc.)
Treatment of Raf-mediated cancers with imidazole derivatives
https://patents.google.com/patent/GB2306108A/en
1997, Etats-Unis (Ontogen Corp)
Imidazole derivatives as MDR modulators
https://patents.google.com/patent/US5840721A/en
1999, Allemagne (Bayer)
Topical composition for preventing radiation-induced skin cancer, e.g. due to sunbathing or radiotherapy, containing azole compound such as bifonazole or clotrimazole
https://patents.google.com/patent/DE19963052A1/en
2001, Etats-Unis (Procter&Gamble)
Amino-imidazole derivatives for treating cancer
https://patents.google.com/patent/WO2001081315A2/en
2006, Etats-Unis (Johns Hopkins)
Use of itraconazole and salts thereof for treating cancer
https://patents.google.com/patent/CA2619889C/en
2008, Chine (Synta Phamaceuticals Corp)
Triazole compounds that are useful in the treatment of proliferative disorders, such as cancer
https://patents.google.com/patent/WO2008097640A2/en
2009, Chine (Guangdong Pharmaceutical University)
Application of imidazole phenanthroline and derivative thereof to preparation of antineoplastic drug
https://patents.google.com/patent/CN101735217A/en
2011, Chine (Guangzhou VMix Investement Co.)
The application of cisplatin combined itraconazole isomer in preparation treatment lung-cancer medicament
https://patents.google.com/patent/CN102319260A/en
2012, Australie (Mayne Pharma International Pty Ltd)
Itraconazole compositions and dosage forms, and methods of using the same
https://patents.google.com/patent/AU2018201298B2/en
2013, Corée du Sud (Industry Academic Cooperation Foundation of Yonsei University )
Novel imidazole derivative and therapeutical use thereof
https://patents.google.com/patent/WO2015046647A1/en
2013, Chine
Itraconazole applied to treatment of malignant tumor or salt thereof and composition thereof
https://patents.google.com/patent/CN103044408A/en
2018, Chine (East China Normal University)
Application of miconazole in the preparation of antitumor drugs
https://patents.google.com/patent/CN110917192A/en
2018, Chine (Sichuan University)
Application of ketoconazole in preparation of medicine for treating liver cancer
https://patents.google.com/patent/CN110772520A/en
2019, Chine (Institute of Dermatology and Skin Disease Hospital of CAMS)
Itraconazole inhibits the application in tumor metastasis medicine in preparation
https://patents.google.com/patent/CN110279696A/en
2020, Chine (Guangdong Pharmaceutical University)
Application of miconazole in preparation of anti-squamous-lung-carcinoma drug and cisplatin sensitizer
https://patents.google.com/patent/CN111067894A/en
2021, Chine (Shantou University Medical College)
Application of sulconazole and/or sulconazole salt in preparing medicine for treating esophageal squamous cell carcinoma
https://patents.google.com/patent/CN113318104A/en
2021, Chine (Guangzhou Medical University)
Application of fenticonazole nitrate in the preparation of anti-tumor drugs
https://patents.google.com/patent/CN114948947B/en
2021, Japon (université Okayama)
Applications for triazole derivatives [rhabdomyosarcoma, neuroblastoma, and Ewing’s sarcoma]
https://patents.google.com/patent/JP2022150578A/en
2022, Chine (université Sichuan)
Combination drug, application and kit for treating oral squamous cell carcinoma
https://patents.google.com/patent/CN115845069B/en
2023, Corée du sud (Sungkyunkwan University Industry-Academic Cooperation Foundation)
Combination therapy for treating drug-resistance cancer using Terconazole
https://patents.google.com/patent/KR20250066808A/en
2024, Arabie Saoudite (King Abdulaziz University )
Imidazole heterocycle based compounds and methods of treating cancer
https://patents.google.com/patent/US20250282764A1/en
2024, Chine (Yunnan Cancer Hospital / Hospital of Kunming Medical University)
Application of clotrimazole in preparing medicine for treating ovarian cancer
https://patents.google.com/patent/CN118021804A/en
ADDENDUM 1
Quand on parle d’antifongiques repositionnés contre le cancer, il ne faut pas penser -seulement- à une action cytotoxique (détruire la cellule malade). En réalité, il s’agit d’un large éventail de propriétés biochimiques.
Les mécanismes proposés dans les brevets incluent :
-inhibition des voies PI3K/Akt (facteur de croissance)
-perturbation des canaux ioniques (pertube les signaux électriques de la cellule)
-inhibition de l’angiogenèse (création de nouveaux vaisseaux sanguins, une spécialité du cancer)
-perturbation du métabolisme mitochondrial
-induction de l’apoptose (mort programmée des cellules)
-sensibilisation aux chimiothérapies
-inhibition de certaines voies de signalisation (Hedgehog pour l’itraconazole, favorise la prolifération de certains cancers solides).
Autre principe de base de la chimie : la potentialisation (augmentation des effets d’une substance en ajoutant une autre substance). Et sans oublier, tout ce que nous ne savons pas encore…
Bref, la règle devrait s’imposer à tous : l’humilité.
Malgré des efforts colossaux, des moyens financiers et techniques stupéfiants étalés sur des décennies, le cancer continue, tragiquement, de se jouer de nous et de se moquer des certitudes rances de Big Cancer.
Au lieu de répéter comme des perroquets empaillés « un vermifuge contre le cancer c’est impossible » ou « un antifongique contre le cancer, c’est absurde« … il faut travailler, expérimenter, chercher à comprendre, être curieux, ouvert d’esprit.
Autrement dit : avoir une -vraie- démarche scientifique.
ADDENDUM 2
En plus des brevets, il existe bien entendu un corpus d’articles, d’études (et mêmes quelques essais cliniques).
Voici une sélection :
1992 : Effects of ketoconazole on the proliferation and cell cycle of human cancer cell lines
https://pubmed.ncbi.nlm.nih.gov/1458471/
2002 : Clotrimazole induced apoptosis in human colon cancer cell line CCL229
https://pubmed.ncbi.nlm.nih.gov/12452064/
2009 : Ketoconazole-induced JNK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells
https://pubmed.ncbi.nlm.nih.gov/19631732/
2010 : Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth
https://pubmed.ncbi.nlm.nih.gov/20385363/
2011 : Itraconazole inhibits angiogenesis and tumor growth in non-small cell lung cancer
https://pubmed.ncbi.nlm.nih.gov/21896639/
2011 : Clotrimazole disrupts glycolysis in human breast cancer without affecting non-tumoral tissues
https://pubmed.ncbi.nlm.nih.gov/21531601/
2013 : Repurposing itraconazole as a treatment for advanced prostate cancer: a noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer
https://pubmed.ncbi.nlm.nih.gov/23340005/
2013 : Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer
https://pubmed.ncbi.nlm.nih.gov/23546045/
2014 : Clotrimazole as a Cancer Drug: A Short Review
https://pubmed.ncbi.nlm.nih.gov/26819835/
2014 : High-dose itraconazole as a noncastrating therapy for a patient with biochemically recurrent prostate cancer
https://pubmed.ncbi.nlm.nih.gov/24332506/
(texte complet dispo sur sci-hub).
2014 : Impact of combination chemotherapy with itraconazole on survival of patients with refractory ovarian cancer
https://pubmed.ncbi.nlm.nih.gov/24778064/
2014 : Impact of itraconazole on the survival of heavily pre-treated patients with triple-negative breast cancer
https://pubmed.ncbi.nlm.nih.gov/24982411/
2014 : The mechanism of bifonazole-induced [Ca(2+)]i rises and non-Ca(2+)-triggered cell death in PC3 human prostate cancer cells
https://pubmed.ncbi.nlm.nih.gov/24849495/
2015 : Repurposing Drugs in Oncology (ReDO)-itraconazole as an anti-cancer agent
https://pubmed.ncbi.nlm.nih.gov/25932045/
2015 : Impact of Itraconazole After First-line Chemotherapy on Survival of Patients with Metastatic Biliary Tract Cancer
https://pubmed.ncbi.nlm.nih.gov/26254389/
2015 : Combination Chemotherapy with Itraconazole for Treating Metastatic Pancreatic Cancer in the Second-line or Additional Setting
https://pubmed.ncbi.nlm.nih.gov/26124377/
2016 : Expression of Hedgehog Signals and Growth Inhibition by Itraconazole in Endometrial Cancer
https://pubmed.ncbi.nlm.nih.gov/26722038/
2016 : Association of Itraconazole, a Hedgehog Inhibitor, and Bladder Cancer
https://pubmed.ncbi.nlm.nih.gov/26812305/
2016 : Suppression of Cancer-associated Fibroblasts and Endothelial Cells by Itraconazole in Bevacizumab-resistant Gastrointestinal Cancer
https://pubmed.ncbi.nlm.nih.gov/26722041/
2017 : Anti-proliferation of breast cancer cells with itraconazole: Hedgehog pathway inhibition induces apoptosis and autophagic cell death
https://pubmed.ncbi.nlm.nih.gov/27810405/
2017 : Itraconazole Inhibits AKT/mTOR Signaling and Proliferation in Endometrial Cancer Cells
https://pubmed.ncbi.nlm.nih.gov/28179296/
2017 : Itraconazole induces apoptosis and cell cycle arrest via inhibiting Hedgehog signaling in gastric cancer cells
https://pubmed.ncbi.nlm.nih.gov/28399898/
2017 : Itraconazole Modulates Hedgehog, WNT/β-catenin, as well as Akt Signalling, and Inhibits Proliferation of Cervical Cancer Cells
https://pubmed.ncbi.nlm.nih.gov/28668841/
2017 : The anti-cancer effects of itraconazole in epithelial ovarian cancer
https://pubmed.ncbi.nlm.nih.gov/28747628/
2017 : Repurposing itraconazole for the treatment of cancer
https://pubmed.ncbi.nlm.nih.gov/28927025/
2017 : Miconazole induces apoptosis via the death receptor 5-dependent and mitochondrial-mediated pathways in human bladder cancer cells
https://pubmed.ncbi.nlm.nih.gov/28498480/
2018 : Itraconazole inhibits invasion and migration of pancreatic cancer cells by suppressing TGF-β/SMAD2/3 signaling
https://pubmed.ncbi.nlm.nih.gov/29484419/
2018 : Itraconazole targets cell cycle heterogeneity in colorectal cancer
https://pubmed.ncbi.nlm.nih.gov/29853607/
2018 : Itraconazole inhibits the proliferation of gastric cancer cells in vitro and improves patient survival
https://pubmed.ncbi.nlm.nih.gov/30127974/
2019 : Itraconazole inhibits proliferation of pancreatic cancer cells through activation of Bak-1
https://pubmed.ncbi.nlm.nih.gov/30260036/
2019 : Miconazole triggers various forms of cell death in human breast cancer MDA-MB-231 cells
https://pubmed.ncbi.nlm.nih.gov/31109399/
2019 : Itraconazole Alters the Stem Cell Characteristics of A549 and NCI-H460 Human Lung Cancer Cells by Suppressing Wnt Signaling
https://pubmed.ncbi.nlm.nih.gov/31833479/
2020 : Flubendazole elicits anti-cancer effects via targeting EVA1A-modulated autophagy and apoptosis in Triple-negative Breast Cancer
https://pubmed.ncbi.nlm.nih.gov/32724459/
2020 : Itraconazole inhibits the Hedgehog signaling pathway thereby inducing autophagy-mediated apoptosis of colon cancer cells
https://pubmed.ncbi.nlm.nih.gov/32681018/
2020 : Anti-fungal drug itraconazole exerts anti-cancer effects in oral squamous cell carcinoma via suppressing Hedgehog pathway
https://pubmed.ncbi.nlm.nih.gov/32407849/
2020 : Itraconazole exerts anti-liver cancer potential through the Wnt, PI3K/AKT/mTOR, and ROS pathways
https://pubmed.ncbi.nlm.nih.gov/32942154/
2020 : Concentration-dependent Early Antivascular and Antitumor Effects of Itraconazole in Non-Small Cell Lung Cancer
https://pubmed.ncbi.nlm.nih.gov/32847935/
2021 : The effect of itraconazole on the clinical outcomes of patients with advanced non-small cell lung cancer receiving platinum-based chemotherapy: a randomized controlled study
https://pubmed.ncbi.nlm.nih.gov/33559053/
2021 : Miconazole induces protective autophagy in bladder cancer cells
https://pubmed.ncbi.nlm.nih.gov/32981224/
2021 : Itraconazole Exerts Its Antitumor Effect in Esophageal Cancer By Suppressing the HER2/AKT Signaling Pathway
https://pubmed.ncbi.nlm.nih.gov/34376577/
2021 : Itraconazole improves survival outcomes in patients with colon cancer by inducing autophagic cell death and inhibiting transketolase expression
https://pubmed.ncbi.nlm.nih.gov/34589147/
2022 : Induced Cell Cycle Arrest in Triple-Negative Breast Cancer by Combined Treatment of Itraconazole and Rapamycin
https://pubmed.ncbi.nlm.nih.gov/35517785/
2022 : Repurposing Oxiconazole against Colorectal Cancer via PRDX2-mediated Autophagy Arrest
https://pubmed.ncbi.nlm.nih.gov/35813474/
2022 : Itraconazole Reverts ABCB1-Mediated Docetaxel Resistance in Prostate Cancer
https://pubmed.ncbi.nlm.nih.gov/35721223/
2022 : Terconazole, an Azole Antifungal Drug, Increases Cytotoxicity in Antimitotic Drug-Treated Resistant Cancer Cells with Substrate-Specific P-gp Inhibitory Activity
https://pubmed.ncbi.nlm.nih.gov/36430288/
2022 : Repurposing econazole as a pharmacological autophagy inhibitor to treat pancreatic ductal adenocarcinoma
https://pubmed.ncbi.nlm.nih.gov/35865101/
2023 : Itraconazole Repolarizes Tumor-associated Macrophages and Suppresses Cervical Cancer Cell Growth
https://pubmed.ncbi.nlm.nih.gov/36697085/
2023 : Action of econazole on Ca2+ levels and cytotoxicity in OC2 human oral cancer cells
https://pubmed.ncbi.nlm.nih.gov/37404653/
2024 : Itraconazole inhibits tumor growth via CEBPB-mediated glycolysis in colorectal cancer
https://pubmed.ncbi.nlm.nih.gov/38278779/
2025 : Itraconazole inhibits the Wnt/β-catenin signaling pathway to induce tumor-associated macrophages polarization to enhance the efficacy of immunotherapy in endometrial cancer
https://pubmed.ncbi.nlm.nih.gov/40697374/
2025 : A Novel Approach to Reducing Chemoresistance in Advanced Ovarian Cancer: The Effect of Itraconazole-A Single-Institution Randomized Placebo-Controlled Trial
https://pubmed.ncbi.nlm.nih.gov/41590341/
2026 : Repurposing Itraconazole in Combination with Chemotherapy and Immune Checkpoint Inhibitor for Cancer
https://pubmed.ncbi.nlm.nih.gov/41718102/
2026 : Oral Administration of Itraconazole Induces M1 Polarization of Tumor-associated Macrophages in Gynecological Cancer
https://pubmed.ncbi.nlm.nih.gov/41760333/
2026 : Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights
https://pubmed.ncbi.nlm.nih.gov/42158746/
2026 : Uncovering the Underlying Mechanism of Clotrimazole against Ovarian Cancer by Transcriptomics and Experimental Investigations
https://pubmed.ncbi.nlm.nih.gov/42478651/
2026 : Design, synthesis, molecular modelling and biological evaluation of oxiconazole-based 1,2,3-triazoles as dually acting antifungal and antitumor agents
https://pubmed.ncbi.nlm.nih.gov/42601411/
2026 : Repurposing butoconazole as a GRP78 substrate-binding domain (SBD) inhibitor to induce endoplasmic reticulum stress–mediated apoptosis in triple-negative breast cancer
https://www.sciencedirect.com/science/article/abs/pii/S0045206826009831
