Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease

Abstract

Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of “stemness”, independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point – a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known “side-effect”, which could be harnessed instead as a “therapeutic effect”. Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.

A mitochondrial based oncology platform for targeting cancer stem cells (CSCs): MITO-ONC-RX

“…These different antibiotics include members of the i) Tetracycline family (Doxycycline/Tigecycline) [16] and the ii) Erythromycin family (Azithromycin) [16], as well as iii) anti-parasitic drugs (Pyrvinium pamoate and Atovaquone) [16,17] and iv) anti-microbials targeting drug-resistant mycobacterium (Bedaquiline; TB, tuberculosis) [18], (Figure 1, and Table 1). …”

“…More specifically, Doxcycyline and Azithromycin inhibit mitochondrial protein translation, effectively blocking new mitochondrial biogenesis [16–20]. Since most tissues already have large numbers of mitochondria (especially skeletal muscle, heart and brain), normal cells remain unaffected.…”

“…In addition, Pyrvinium pamoate and Atovaquone behave as mitochondrial OXPHOS inhibitors, affecting Complexes II and III [16,17]. Bedaquiline inhibits the mitochondrial ATP-synthase (Complex V) [18].…”

Repurposing of Anthelminthics as Anticancer Drugs

“…In particular, glucose utilization and related unfolded protein response as well as autophagy were reported to become deranged in diverse cancer cells [8,72,73]. Pyrvinium-induced cell death was associated with defective mitochondrial respiration in diverse cancers, breast CSC-like cells and lymphoma, the latter involving regulation of JAK2/STAT5 signaling [60,[68][69][70]. Several studies reported the Wnt pathway as target of pyrvinium, especially in breast and lung CSCs [56,63,64].…”

Studies on antitumor activity spectrum of doxycycline

“…[1][2][3][4] Four to five classes of drugs, such as tetracyclines, can also be used to eradicate 12 cancer cell lines. [5] Tetracyclines are cytotoxic to tumor cells. [6] As a semi-synthetic tetracycline, doxycycline inhibits matrix metalloproteinase (MMP) activation, prevents cell proliferation, and downregulates DNA-dependent protein kinase.…”