Glycyrrhetinic Acid as a Hepatocyte Targeting Ligand-Functionalized Platinum(IV) Complexes for Hepatocellular Carcinoma Therapy and Overcoming Multidrug Resistance.

Promising targeted therapy options to overcome drug resistance and side effects caused by platinum(II) drugs for treatment in hepatocellular carcinoma are urgently needed. Herein, six novel multifunctional platinum(IV) complexes through linking platinum(II) agents and glycyrrhetinic acid (GA) were designed and synthesized. Among them, complex 20 showed superior antitumor activity against tested cancer cells including cisplatin resistance cells than cisplatin and simultaneously displayed good liver-targeting ability. Moreover, complex 20 can significantly cause DNA damage and mitochondrial dysfunction, promote reactive oxygen species generation, activate endoplasmic reticulum stress, and eventually induce apoptosis. Additionally, complex 20 can effectively inhibit cell migration and invasion and trigger autophagy and ferroptosis in HepG-2 cells. More importantly, complex 20 demonstrated stronger tumor inhibition ability than cisplatin or the combo of cisplatin/GA with almost no systemic toxicity in HepG-2 or A549 xenograft models. Collectively, complex 20 could be developed as a potential anti-HCC agent for cancer treatment.

Dual-targeting tumor cells hybrids derived from Pt(IV) species and NF-κB inhibitors enables cancer therapy through mitochondrial dysfunction and ER stress and overcomes cisplatin resistance.

To ameliorate the defects including serious side effects and drug resistance of Pt(II) drugs (e.g., cisplatin and oxaliplatin), here a novel of "dual-prodrug" by containing Pt(II) drugs and NF-κB inhibitors were synthesized and characterized. Among them, Pt(IV) complex 11 exhibited better cytotoxic activity than other Pt(IV) complexes and the corresponding Pt(II) drugs, with IC50 values ranged from 0.31 to 0.91 µM, respectively, and also displayed low toxicity toward two normal cells HL-7702 and BEAS-2B. More importantly, complex 11 significantly reversed cisplatin resistance in A549/CDDP cells, indicating that complex 11 was able to overcome multidrug resistance. Following mechanism studies demonstrated that complex 11 significantly induced DNA damage and ROS generation, arrest the cell cycle at the G2/M stage, suppressed cell migration and intrusion, and induced cell apoptosis through activated ER stress and mitochondrial apoptosis pathway in A549 cells. Moreover, complex 11 effectively suppressed the IKKß phosphorylation, IκBα phosphorylation and NF-κB p65 phosphorylation and nuclear translocation, leading to blocked the NF-κB signal pathway in A549 cells. In vivo tests showed that the inhibitory rate in the complex 11 reached 69.2 %, which was much higher than that of oxaliplatin (55.6 %), 1a (39.7 %) and the combination of oxaliplatin/1a (65.1 %), without causing loss in the body weight.

Novel combretastatin A-4 derivative containing aminophosphonates as dual inhibitors of tubulin and matrix metalloproteinases for lung cancer treatment.

Here, sixteen novel conjugates containing tubulin inhibitor and matrix metalloproteinase inhibitor was synthesized together with their activity evaluated. Among them, 9e exhibited the most potent activity against various human cancer cells (IC50 values was 0.19-0.42 µM) as well as multidrug-resistant tumor cells (A549/CDDP and MCF-7/DOX) and also showed significantly lower cytotoxic activity toward human normal liver cells LO2 in comparison with that of CA-4. Interestingly, 9e not only strongly inhibited tubulin polymerization, and induced cell apoptosis and cell cycle arrest in G2/M stage, but also remarkably displayed inhibition of cell migration against A549 cells in vitro, and exhibited a moderate activity toward MMP-2, MMP-3 and MMP-9, respectively. Moreover, the significant down-regulation in the levels of Bcl-2 protein and up-regulated levels of proteins, such as Bax, p53 and caspase-3, indicated that 9e can induce apoptosis via mitochondria-dependent apoptosis pathway. Additionally, 9e can also cause ER stress demonstrating as up-regulation express of proteins (CHOP, p-eIF2a, and p-PERK). Importantly, 9e displayed significant in vivo antitumor efficacy in A549 xenograft models without inducing apparent systemic toxicity. Collectively, this work indicated that compound 9e, a dual MMPs and tubulin inhibitor, is a novel and promising agent for cancer therapy.