Abstract
Here, we developed a new synthetic lethal strategy for further optimizing the eradication of cancer stem cells (CSCs). Briefly, we show that chronic treatment with the FDA-approved antibiotic Doxycycline effectively reduces cellular respiration, by targeting mitochondrial protein translation. The expression of four mitochondrial DNA encoded proteins (MT-ND3, MT-CO2, MT-ATP6 and MT-ATP8) is suppressed, by up to 35-fold. This high selection pressure metabolically synchronizes the surviving cancer cell sub-population towards a predominantly glycolytic phenotype, resulting in metabolic inflexibility. We directly validated this Doxycycline-induced glycolytic phenotype, by using metabolic flux analysis and label-free unbiased proteomics.Next, we identified two natural products (Vitamin C and Berberine) and six clinically-approved drugs, for metabolically targeting the Doxycycline-resistant CSC population (Atovaquone, Irinotecan, Sorafenib, Niclosamide, Chloroquine, and Stiripentol). This new combination strategy allows for the more efficacious eradication of CSCs with Doxycycline, and provides a simple pragmatic solution to the possible development of Doxycycline-resistance in cancer cells. In summary, we propose the combined use of i) Doxycycline (Hit-1: targeting mitochondria) and ii) Vitamin C (Hit-2: targeting glycolysis), which represents a new synthetic-lethal metabolic strategy for eradicating CSCs.This type of metabolic Achilles’ heel will allow us and others to more effectively “starve” the CSC population.
Highlights
Cancer stem cells (CSCs) are thought to be the “root cause” of tumor recurrence, distant metastasis and therapy-resistance, driving poor clinical outcome in advanced cancer patients [1,2,3]
We show here that DoxyR cancer stem cells (CSCs) are between 4- to 10-fold more susceptible to the effects of Vitamin C, inhibiting their propagation in the range of 100 to 250 μM
We suggest a new synthetic lethal strategy for eradicating CSCs, by employing i) Doxycycline and ii) Vitamin C (Figure 12)
Summary
Cancer stem cells (CSCs) are thought to be the “root cause” of tumor recurrence, distant metastasis and therapy-resistance, driving poor clinical outcome in advanced cancer patients [1,2,3]. New therapeutic strategies are necessary to identify and eradicate CSCs [47]. As such, this goal remains an unmet medical need. High mitochondrial mass is a surrogate marker for increased mitochondrial biogenesis and/or elevated mitochondrial protein translation. This simple metabolic observation provides a new means for both i) CSC identification [9,10,11,12,13] and ii) CSC eradication [9, 10, 14,15,16,17,18,19]
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