Platinum(IV) Complexes as Inhibitors of STAT3 and Regulators of the Tumor Microenvironment To Control Breast Cancer

Interplay between breast cancer (BC) cells and the tumor
microenvironment
(TME) influences the outcome of cancer treatment. Aberrant activation
of signal transducer and activator of transcription 3 (STAT3) promotes
the interaction and causes immunosuppression and drug resistance.
Platinum(IV) complexes SPP and DPP bearing pterostilbene-derived axial
ligand(s) were synthesized to inhibit the JAK2-STAT3 pathway in BC
cells and regulate the TME. These complexes exerted remarkable antiproliferative
activity against the triple-negative BC cells, suppressed the expression
of phosphorylated STAT3 and STAT3-related cyclooxygenase-2 and IL-6,
and activated caspase-3 and cleaved poly ADP-ribose polymerase, preventing
the repair of DNA lesions and inducing apoptosis. Furthermore, DPP
promoted the maturation and antigen presentation of dendritic cells,
repressed the proliferation and differentiation of myeloid-derived
suppressor cells and regulatory T cells, and facilitated the expansion
of T cells. As a consequence, DPP showed excellent anticancer activity
against BC with almost no general toxicity in vivo as a potential
chemoimmunotherapeutic agent.

乳腺癌（breast cancer, BC）细胞与肿瘤微环境（tumor microenvironment, TME）之间的相互作用，可影响癌症治疗的转归。信号转导与转录激活因子3（signal transducer and activator of transcription 3, STAT3）的异常激活，会促进二者的相互作用，并引发免疫抑制与耐药性。本研究合成了带有紫檀茋衍生轴向配体的铂(IV)配合物SPP与DPP，旨在抑制乳腺癌细胞中的JAK2-STAT3通路并调控肿瘤微环境。此类配合物对三阴性乳腺癌细胞展现出显著的抗增殖活性：可抑制磷酸化STAT3以及STAT3相关的环氧合酶-2与白细胞介素-6（interleukin-6, IL-6）的表达，激活半胱天冬氨酸蛋白酶-3（caspase-3）与切割型聚腺苷二磷酸核糖聚合酶，进而阻碍DNA损伤修复并诱导细胞凋亡。此外，DPP可促进树突状细胞的成熟与抗原呈递，抑制髓系来源抑制细胞与调节性T细胞的增殖与分化，并推动T细胞的扩增。综上，作为一款潜在的化学免疫治疗药物，DPP在体内展现出优异的抗乳腺癌活性，且几乎无全身性毒性。