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2015 ; 6
(7
): 4569-84
Nephropedia Template TP
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Antibiotics that target mitochondria effectively eradicate cancer stem cells,
across multiple tumor types: treating cancer like an infectious disease
#MMPMID25625193
Lamb R
; Ozsvari B
; Lisanti CL
; Tanowitz HB
; Howell A
; Martinez-Outschoorn UE
; Sotgia F
; Lisanti MP
Oncotarget
2015[Mar]; 6
(7
): 4569-84
PMID25625193
show ga
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.