"Warburg Effect" shows that most
tumor cells rely on aerobic glycolysis for energy supply, leading to malignant energy deprivation and an "internal alkaline external
acid" tumor microenvironment. Destructing the "Warburg Effect" is an effective approach to inhibit
tumor progression. Herein, an acidity-responsive nanoreactor (Au@CaP-Flu@HA) is fabricated for toxic
acidosis and
starvation synergistic
therapy. In the nanoreactor, the
fluvastatin (Flu) could reduce
lactate efflux by inhibiting the
lactate-
proton transporter (monocarboxylate transporters, MCT4), resulting in intracellular
lactate accumulation. Meanwhile, the
glucose oxidase-mimic Au-nanocomposite consumes
glucose to induce cell
starvation accompanied by
gluconic acid production, coupling with
lactate to exacerbate toxic
acidosis. Also, the up-regulated autophagic energy supply of
tumor cells under energy deprivation and
hypoxia aggravation is blocked by autophagy inhibitor CaP. Cellular dysfunction under pHi acidification and impaired
Adenosine Triphosphate (
ATP) synthesis under
starvation synergistically promote
tumor cell apoptosis. Both in vitro and in vivo studies demonstrate that this combinational approach of toxic-
acidosis/
starvation therapy could effectively destruct the "Warburg Effect" to inhibit
tumor growth and anti-metastatic effects.