IV Vitamin C and Doxycycline in treating cancer by targeting Cancer Stem Cells
A formidable team of researchers from the University of Calabria, University of Manchester, and University of Salford has made a groundbreaking revelation in the ongoing war against cancer. Their innovative, "synthetic lethal" strategy pairs an FDA-approved antibiotic, Doxycycline, with a common dietary supplement, Vitamin C, in a strategic bid to target and eliminate cancer stem cells (CSCs) by harnessing their metabolic vulnerabilities.
Doxycycline, a well-established pharmaceutical, has shown its prowess in the field of cancer therapy. With its near-complete absorption and reliable half-life, it boasts impressive pharmacokinetic qualities. Yet, like any therapeutic agent, the specter of drug-resistance remains an ever-present concern. The study shows that cancer cells can evade the effects of Doxycycline, adopting a purely glycolytic phenotype—an energy production mechanism that prefers glucose as its primary fuel. In this scenario, one might anticipate a dead-end, but it is here where the combined therapy shines, turning the tables on the evasive cancer cells.
This metabolic inflexibility of Doxycycline-resistant (DoxyR) CSCs plays into the hands of our dynamic duo: Vitamin C, adept at blocking aerobic glycolysis, swoops in to target these cancer cells. Previous studies have shown Vitamin C to be an inhibitor of GAPDH (a glycolytic enzyme) and to deplete glutathione, a cellular antioxidant, thereby escalating reactive oxygen species (ROS) production and oxidative stress. It's revealed that DoxyR CSCs are up to ten times more susceptible to Vitamin C, thereby impeding their propagation. In essence, Vitamin C and Doxycycline, in concert, provide a novel synthetic lethal drug combination, taking aim at both mitochondrial and glycolytic metabolism to annihilate CSCs.
To fine-tune this lethal strategy, the researchers chronically treated CSCs with Doxycycline, causing a decrease in cellular respiration and targeting mitochondrial protein translation. As a result, four mitochondrial DNA encoded proteins' expression was curtailed by up to 35-fold. This forced the remaining cancer cells towards a predominantly glycolytic phenotype, causing metabolic inflexibility. The researchers corroborated this Doxycycline-induced metabolic state through metabolic flux analysis and label-free unbiased proteomics.
In addition to Vitamin C, Berberine, another natural product, was identified along with six FDA-approved drugs (Atovaquone, Irinotecan, Sorafenib, Niclosamide, Chloroquine, and Stiripentol), all capable of metabolically targeting Doxycycline-resistant CSC population. This combination strategy improves the chances of eradicating CSCs with Doxycycline while offering a practical solution to potential Doxycycline-resistance in cancer cells.
The researchers propose the combined application of Doxycycline, which targets mitochondria, and Vitamin C, which targets glycolysis, as a new synthetic-lethal metabolic strategy to eliminate CSCs. This cleverly orchestrated attack targets the cancer cells' metabolic Achilles' heel, effectively "starving" the CSC population.
Moreover, the researchers have developed an alternative three-pronged attack using Doxycycline, Azithromycin, and Vitamin C. This strategy, while focusing on inducing a "rho-zero-like" phenotype in cancer cells, has been seen to greatly inhibit CSC propagation using the MCF7 ER(+) breast cancer cell line.
By exploiting the metabolic inflexibility of CSCs, the researchers have conceived a versatile strategy for their elimination, wielding Doxycycline's mitochondrial inhibition effects, and the glycolysis blockade caused by Vitamin C and other FDA-approved drugs. This exciting new synthetic lethal strategy promises more effective targeting and eradication of CSCs, providing a beacon of hope in our ongoing battle against cancer.