phenanthrenes and Triple-Negative-Breast-Neoplasms

Salvia miltiorrhiza Bunge (Danshen), has been used for its therapeutic value in Traditional Chinese Medicine (TCM), for almost a thousand years. Dihydrotanshinone-I (DHTS) is a lipophilic compound isolated from the plant Salvia miltiorrhiza that has been shown to induce anti-proliferative and apoptotic effects on breast cancer cells. In the present study, we investigated the anti-migratory effect of DHTS on TNBC cell lines by studying the Epithelial Mesenchymal Transition (EMT) changes.. IC50 values for DHTS in TNBC breast cancer cells were either discovered by literature search or by performing MTT assay. DHTS effect on EMT markers (viz. CD44, E-cadherin, Vimentin, N-cadherin, and active β-catenin) was studied using western blotting. Association between EMT and migration was further carried out in DHTS treated TNBC cells by wound healing assay. Cancer stemness and proliferation potential were further accessed using colony formation assay.. MTT assay revealed IC50 of MDA-MB-468 cells at 2 µM for 24 h. Subsequently, DHTS treatment in TNBC cell lines (MDA-MB-468 and MDA-MB-231) led to decrease in mesenchymal markers i.e. vimentin, N-cadherin and, active β-catenin. DHTS treated MDA-MB-468 cells showed a decrease in adhesion protein CD44 and an increase in epithelial protein E-cadherin. Additionally, a decrease in EMT potential was positively associated with the inhibition of migration and clonogenic potential in DHTS treated TNBC cells.. In this study, we have demonstrated for the first time that DHTS has the potential to inhibit the migration and clonogenicity of highly aggressive TNBC cells by obstructing Epithelial to Mesenchymal Transition.

Topics: Biomarkers, Tumor; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Furans; Humans; Phenanthrenes; Plant Extracts; Quinones; Triple Negative Breast Neoplasms

Triple-negative breast cancer (TNBC) lacks three important receptors, ER, PR, and HER2. It is more aggressive and more likely to relapse after treatment, thus has been identified as one of the most malignant breast cancer types. The development of efficient targeted TNBC therapy is an important research topic in TNBC treatment. We report the development of a new aptamer-drug conjugate (ApDC), AS1411-triptolide conjugate (ATC), as targeted therapy for the treatment of TNBC with high efficacy. The conjugate possesses excellent specificity and high cytotoxicity against the MDA-MB-231 cell line. The advantages of our newly invented ATC are further highlighted by its excellent 

Topics: Animals; Antineoplastic Agents; Apoptosis; Aptamers, Nucleotide; Cell Line, Tumor; Cell Proliferation; Diterpenes; Epoxy Compounds; Female; Humans; Mice; Phenanthrenes; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Species in the Juncaceae accumulate different types of secondary metabolites, among them phenanthrenes and 9,10-dihydrophenanthrenes in substantial amounts. These compounds have chemotaxonomic significance and also possess interesting pharmacological activities. The present study has focused on the isolation, structure determination, and pharmacological investigation of phenanthrenes from

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Humans; Magnoliopsida; Mice; Molecular Structure; Phenanthrenes; Plant Extracts; Salt-Tolerant Plants; Tetrazolium Salts; Thiazoles; Triple Negative Breast Neoplasms

Triptolide is a natural compound isolated from the Tripterygium wilfordii, which possesses anti-inflammatory and anti-tumor activities. Triptolide reportedly inhibits RNA polymerase II-mediated transcription and ATM activities to interfere with DNA repair. However, the roles of triptolide in DNA repair are still largely unknown. Triple negative breast cancer cells (TNBC) are insensitive to targeted anti-tumoral drugs, thus DNA damage chemotherapeutic drugs are the available treatments used in clinic, while the drug resistance of TNBC causes the challenge for successful cure. In this study, we investigated the efficiency of cisplatin in combination with triptolide in treatment of TNBC. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay shows triptolide suppresses the growth of two triple-negative breast cancer cells, BT549 and MDA-MB-231. Triptolide induces DNA breaks and arrests TNBC in the cell cycle S phase, and sensitizes TNBC to cisplatin. Western blot analysis shows triptolide down-regulated the levels of PARP1 and XRCC1, and slightly decreases the levels of RAD51. The results demonstrate triptolide interferes with single strand-break and base excision repair. The over-expressed PARP1/XRCC1 help the TNBC to resist triptolide. Based on these results, we conclude triptolide confers sensitization of TNBC to cisplatin via interference with XRCC1/PARP1-mediated base excision repair.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cisplatin; Diterpenes; DNA Damage; DNA Repair; Epoxy Compounds; Female; Gene Expression Regulation, Neoplastic; Humans; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Triple Negative Breast Neoplasms; X-ray Repair Cross Complementing Protein 1

Silencing STAT3 is confirmed as a promising therapeutic strategy for triple-negative breast cancer (TNBC) therapy to address the issue of its poor prognosis. In this study, the natural product cryptotanshinone was firstly remodeled and modified as a more effective STAT3 inhibitor by structure-based strategy. The synthetic derivative KYZ3 had 22-24-fold increase in antitumor activity than cryptotanshinone on two TNBC cell lines but had little effect on normal breast epithelial MCF-10A cells. Further investigation showed that KYZ3 inhibited persistent STAT3 phosphorylation. It also prevented the STAT3 protein nuclear translocation to regulate the expressions of the target oncogenes including Bax and Bcl-2. Furthermore, KYZ3 inhibited TNBC cell metastasis by decreasing the levels of MMP-9 which were directly regulated by activated STAT3. A STAT3 plasmid transfecting assay suggested that KYZ3 induced tumor cell apoptosis mainly by targeting STAT3. Finally, KYZ3 suppressed the growth of tumors resulting from subcutaneous implantation of MDA-MB-231 cells in vivo. Taken together, KYZ3 may be a promising cancer therapeutic agent for TNBC.

Topics: Active Transport, Cell Nucleus; Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Cell Movement; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Phenanthrenes; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; STAT3 Transcription Factor; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

There is mounting evidence that cancer stem-like cells (CSC) are selectively enriched in residual tumors after anticancer therapies, which may account for tumor recurrence and metastasis by regenerating new tumors. Thus, there is a critical need to develop new therapeutic agents that can effectively eliminate drug-resistant CSCs and improve the efficacy of cancer therapy. Here, we report that Triptolide (C1572), a small-molecule natural product, selectively depletes CSCs in a dose-dependent fashion in human triple-negative breast cancer (TNBC) cell lines. Nanomolar concentrations of C1572 markedly reduced c-MYC (MYC) protein levels via a proteasome-dependent mechanism. Silencing MYC expression phenocopied the CSC depletion effects of C1572 and induced senescence in TNBC cells. Limited dilution assays revealed that

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Diterpenes; Drug Resistance, Neoplasm; Epoxy Compounds; Female; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Recurrence, Local; Neoplastic Stem Cells; Phenanthrenes; Proto-Oncogene Proteins c-myc; RNA Interference; RNA, Small Interfering; Spheroids, Cellular; Triple Negative Breast Neoplasms; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Novel N(3)-substituted 9,10-Phenanthrenequinone thiosemicarbazones and their copper, nickel and palladium complexes are structurally characterized and reported along with the single crystal X-ray structures of three ligands and one nickel complex. All compounds were evaluated for their antiproliferative potential against Triple Negative Breast Cancer (TNBC) cells which have poor prognosis and no effective drugs to treat with. All compounds exhibited antiproliferative activity against these cells. Among the metal complexes evaluated, redox active copper complexes were found to be more potent. The possible mechanism for such enhanced activity can be attributed to the generation of oxidative stress, which was amenable for targeting through metal complexation.

Topics: Antineoplastic Agents; Breast; Cell Line, Tumor; Cell Proliferation; Coordination Complexes; Copper; Female; Humans; Models, Molecular; Phenanthrenes; Thiosemicarbazones; Triple Negative Breast Neoplasms