ABSTRACT
An octahedral Pt (IV) prodrug, Cis-wog, containing a wogonin derivative as a bioactive axial ligand was designed and prepared to suppress DDR (DNA damage repair)-related proteins. In vitro biological studies indicated that a Pt (IV) prodrug with axially functional groups (Cis-wog) showed cytotoxicity superior to cisplatin and reversed its resistance against two pairs of cisplatin sensitive and resistant cell lines. Further mechanistic research revealed that the powerful antitumor activity of Cis-wog resulted from its suppression of JWA and its multi-interaction with XRCC1 to repair DNA single strand breaks (SSBs) caused by the introduction of wogonin. It is concluded that Cis-wog is a promising cytotoxic agent, which could be used for enhancing the antitumor activity of its corresponding Pt(II)-based drugs and reversing cisplatin resistance via decaying JWA-mediated SSBs repair pathways and inducing apoptosis.
Subject(s)
Antineoplastic Agents/pharmacology , Cisplatin/pharmacology , DNA Repair/drug effects , Drug Resistance, Neoplasm/drug effects , Flavanones/pharmacology , A549 Cells , Apoptosis , Cell Line, Tumor , Humans , Organoplatinum Compounds/pharmacology , Prodrugs/pharmacology , X-ray Repair Cross Complementing Protein 1/metabolismABSTRACT
Two Pt(IV) prodrugs, Cx-platin-Cl and Cx-DN604-Cl, derived from the conjugation of cisplatin or DN604 with a CK2 inhibitor CX-4945, were constructed to suppress DNA damage repair-related elements. During in vitro biological studies, the Pt(IV) prodrugs had excellent cytotoxicity superior to cisplatin and DN604 to reverse drug resistance. Further mechanistic investigations revealed that the powerful anticancer activity of Cx-platin-Cl and Cx-DN604-Cl arisen from its suppression of JWA-XRCC1-mediated single-strand breaks repair. The emerging Pt(IV) prodrugs inhibited the growth of the xenografted tumors of C57BL6 and nude mice apart from JWA-/- mice. Between them, Cx-platin-Cl augmented the infiltration and proliferation of Teff cells, alleviated the recruitment of Treg cells. The results provided compelling preclinical support that Cx-platin-Cl and Cx-DN604-Cl could reverse chemo-immune resistance via decaying JWA-XRCC1-mediated SSBR and immunosuppression, improving the development of emerging Pt(IV) candidate as a potential immunotherapeutic agent for cancer resistant prevention.
Subject(s)
Antineoplastic Agents/therapeutic use , Heat-Shock Proteins/metabolism , Membrane Transport Proteins/metabolism , Naphthyridines/therapeutic use , Neoplasms/drug therapy , Organoplatinum Compounds/therapeutic use , Prodrugs/therapeutic use , Animals , Antineoplastic Agents/chemistry , Cell Line, Tumor , DNA Breaks/drug effects , Drug Resistance, Neoplasm/drug effects , Humans , Immune Tolerance/drug effects , Mice, Inbred C57BL , Mice, Nude , Naphthyridines/chemistry , Neoplasms/immunology , Neoplasms/metabolism , Organoplatinum Compounds/chemistry , Phenazines , Prodrugs/chemistry , X-ray Repair Cross Complementing Protein 1/metabolismABSTRACT
The anticancer mechanism of NO is difficult to study owing to its short lifetime and high reactivity. Thus, a theranostic anticancer NO donor assembled with NO on-demand release abilities, accurate lysosome location capabilities and signal feedback behavior was developed. Profiting from the theranostic properties, the specific mechanism was comprehensively studied. Spectral and cell imaging studies revealed that the as prepared NO donors could release NO in solution or within cancer cells. Fluorescence co-dyeing experiments demonstrated that Mo-Nap-NO entered lysosomes specifically and disrupted them after being triggered by light. Upon irradiation with 460 nm visible light, both the donors demonstrated considerable in vitro anticancer effects. A further mechanistic study showed that after entering the lysosome and being triggered by 460 nm irradiation, NO ruptured the lysosome, resulting in the release of cathepsin D into the cytosol, which activated the caspase3 mediated apoptosis pathway.
Subject(s)
Antineoplastic Agents/pharmacology , Fluorescent Dyes/pharmacology , Lysosomes/metabolism , Naphthalimides/pharmacology , Nitric Oxide Donors/pharmacology , Nitrosamines/pharmacology , Antineoplastic Agents/radiation effects , Cell Line, Tumor , Fluorescence , Fluorescent Dyes/radiation effects , Humans , Light , Naphthalimides/radiation effects , Nitric Oxide Donors/radiation effects , Nitrosamines/radiation effects , Theranostic Nanomedicine/methodsABSTRACT
DN604, containing a functional dicarboxylato ligand as carboplatin analogue, was significantly studied to explore its potency of antitumour activity. In vitro and in vivo experimental evidence indicated that DN604 exhibited superior antitumor activity than present platinum(II)-based agents in cervix squamous carcinoma SiHa cancer cells. Moreover, DN604 showed negligible toxic effects in vivo as confirmed as Pt accumulation and body weights of mice. Mechanistic studies have shown that DN604 suppressed CK2-mediated MRN complex to improve its antitumor efficacy by promoting DNA double-strand breaks repair. Furthermore, DN604 could inhibit Beclin1 and attenuate CK2-mediated several DSBs repair-related pathways, thus leading to cell apoptosis. Taken together, our research demonstrated that DN604 with the functional dicarboxylato ligand as the leaving group could effectively enhance chemo-sensitivity of SiHa cells to platinum-based agents via suppressing Beclin1 and CK2-mediated MRN-DSBs repair.
Subject(s)
Acid Anhydride Hydrolases/antagonists & inhibitors , Beclin-1/metabolism , Carboplatin/analogs & derivatives , Casein Kinase II/antagonists & inhibitors , Cell Cycle Proteins/antagonists & inhibitors , DNA Breaks, Double-Stranded , DNA-Binding Proteins/antagonists & inhibitors , MRE11 Homologue Protein/antagonists & inhibitors , Nuclear Proteins/antagonists & inhibitors , Uterine Cervical Neoplasms/drug therapy , Animals , Apoptosis , Beclin-1/genetics , Biomarkers, Tumor , Carboplatin/pharmacology , Cell Cycle , Cell Proliferation , DNA Repair , Female , Gene Expression Regulation, Neoplastic , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Tumor Cells, Cultured , Uterine Cervical Neoplasms/metabolism , Uterine Cervical Neoplasms/pathology , Xenograft Model Antitumor AssaysABSTRACT
As the first intracellular signaling molecule and the most frequently mutated oncogene, B-Raf represents an important target in cancer therapy. Here we report several pomalidomide hybrids acting as proteolysis targeting chimeras (PROTACs) for the degradation of B-Raf. Due to its high expression of B-Raf, MCF-7 cells are sensitive to these compounds. Among them, compound 2 can effectively kill cancer cells via inducing cells apoptosis. As a B-Raf degrader, compound 2 can accelerate the degradation of B-Raf by recruiting ubiquitin-proteasome system, and further affects the expression of Mcl-1, a downstream protein of B-Raf. The anticancer mechanism of compound 2 is quite different from its mother compound and cancer cells seem to be more sensitive to the degrader, hinting that degradation of B-Raf by PROTAC is a potential way for cancer treatment.