Natural Product Albiziabioside A Conjugated with Pyruvate Dehydrogenase Kinase Inhibitor Dichloroacetate To Induce Apoptosis-Ferroptosis-M2-TAMs Polarization for Combined Cancer Therapy

The reprogramming of energy metabolism
is considered to be one
of the main characteristics of cancer. The development of therapeutic
agents targeting glycolysis to alter aberrant glucose metabolism and
restore oxidative phosphorylation has emerged as an effective approach
for cancer therapy. In this way, we have developed a conjugate AlbA-DCA,
which can induce a marked increase in intracellular ROS and alleviate
the accumulation of lactic acid in TME. Meanwhile, AlbA-DCA selectively
kills cancer cells and exhibits an excellent synergistic effect. Mechanism
studies confirm that AlbA-DCA can induce apoptosis and ferroptosis.
We also confirm that AlbA-DCA can remold the tumor immunosuppression
microenvironment via eliminating M2-TAMs to inhibit both primary and
distal tumor progression in a dual-4T1 tumor model in female BALB/c
mice. As a result, rational design of natural saponin and PDK inhibitor
to induce apoptosis-ferroptosis-M2-TAMs polarization for enhanced
cancer therapy is a promising strategy, thus providing a new idea
for cancer therapy.