LWJ-M30, a conjugate of DM1 and B6, for the targeted therapy of colorectal cancer with improved therapeutic effects.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide as well as a significant cause of mortality. The conventional treatment could cause serious side effects and induce drug resistance, recurrence and metastasis of cancers. Hence, specific targeting of cancer cells without affecting the normal tissues is currently an urgent necessity in cancer therapy. The emerging of peptide-drug conjugates (PDC) is regarded as a promising approach to address malignant tumors. LWJ-M30, a conjugate of DM1 and B6 peptide, targeted transferrin receptors (TfRs) on the surface of the CRC cells, showing a powerful anti-cancer effect. LWJ-M30 significantly inhibited the HCT116 cells proliferation and migration in vitro. LWJ-M30 also dramatically decreased the level of polymeric tubulin, while the disruption of microtubules caused the cell cycle to be arrested in the G2/M phase. LWJ-M30 induced the HCT116 cells apoptosis both in vivo and in vitro. The results in vivo demonstrated that LWJ-M30 could inhibit the HCT116 growth without affecting the mouse body weight. Taking these results together, our data indicated that LWJ-M30 could improve the therapeutic effects of DM1 while reducing the systemic toxicity in normal tissues.

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.

Novel antitumor compound optimized from natural saponin Albiziabioside A induced caspase-dependent apoptosis and ferroptosis as a p53 activator through the mitochondrial pathway.

It is highly desirable to activation p53 function with small-molecule compounds for colon cancer therapy. Triterpene saponin has been characterized with the favorable selectivity and safety profiles. However, the application of triterpene saponin as cancer chemotherapy drugs was hampered primarily by moderate anticancer potency and the lack the mechanism of action. In this study, we synthesized a series of Albiziabioside A derivatives and evaluated the antitumor activity both in vitro and in vivo. Compounds D13 possessed strong inhibitory activity against HCT116 cells with IC50 values of 5.19 µM. More importantly, compound D13 had a favorable selectivity and was efficacious against MDR cancer cells. Moreover, compound D13 could induce apoptosis and ferroptosis through the mitochondrial pathway as a p53 activator. In addition, compound D13 significantly suppressed tumorigenesis without inducing toxicity in normal organs in vivo. Collectively, this study provides a clinically relevant argument for considering triterpene saponin derivatives D13 as potential cancer therapeutic candidates with enhanced activity, acceptable safety and novel mechanisms of action. To the best of our knowledge, this compound is the first drug candidate which can induce apoptosis and ferroptosis as a p53 activator.

Natural product-based design, synthesis and biological evaluation of Albiziabioside A derivatives that selectively induce HCT116 cell death.

A series of Albiziabioside A coupled substituents of cinnamoyl derivatives were designed and synthesized. The synthesized compounds were screened for anticancer activity against a panel of six human cancer cell lines using a MTT assay. Synthetic derivatives showed excellent selectivity, as they were toxic against only HCT116 cell line. Some compounds exhibited better anti-cancer activity against HCT116 compared to positive controls, such as 5-fluorouracil and Albiziabioside A. Compound 8n was the most active derivative. Importantly, it was also found that the anti-proliferative activity of 8n could be attributed to the induction of cell cycle arrest and apoptosis in HCT116 cells.

A library of 1,2,3-triazole-substituted oleanolic acid derivatives as anticancer agents: design, synthesis, and biological evaluation.

A series of novel oleanolic acid coupled 1,2,3-triazole derivatives have been designed and synthesized by employing a Cu(I) catalyzed Huisgen 1,3-dipolar cycloaddition reaction. The anti-proliferative evaluation indicated that some compounds exhibited excellent anti-cancer activity against the examined cancer cell lines. Among all derivatives, compound 3t possesses the best inhibitory activity against HT1080 cells. A series of pharmacology experiments show that compound 3t significantly induced HT1080 cell apoptosis. Therefore, this compound can serve as a promising lead candidate for further study.