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Ten ingenane-type diterpenoids, including two undescribed compounds named as kansuininols A–B (1–2), were isolated from the roots of Euphorbia kansui. Their structures were elucidated by detailed interpretation of their spectroscopic data, especially 2D-NMR and HR-ESI-MS. Chemoreversal assays of these isolates were carried on adriamycin resistant human breast adenocarcinoma cell line MCF-7/ADR, and compounds 1–2 were identified as potent low-cytotoxic MDR modulators with greater chemoreversal ability than the positive drug verapamilti.

Chemotherapeutic resistance is a major obstacle to control of advanced breast cancer (BCa). We have previously shown that small extracellular vesicles (sEVs) can transmit adriamycin resistance between BCa cells. Here, we demonstrate that sEV-TGF-involves in intercellular drug-resistant transmission from adriamycin-resistant cells to adriamycin-sensitive cells. sEVs were isolated and characterized form the both sensitive and resistant cells. sEVs derived from the resistant cells were incubated with the sensitive cells and resulted in transmitting the resistant phenotype to the recipient cells. Cytokine antibody microarray revealed that most metastasis associated cytokines present at the high levels in sEVs from the resistant cells compared to their levels in sEVs from the sensitive cells, particularly TGF-β1. The sEV-TGF-β1 led to phosphorylation of Smad2/3 and remarkably changed the phenotypes of the recipient cells by suppressing apoptosis and enhancing cell movability. Finally, the sEV-TGF-mediated drug-resistance transmission was validated using a zebrafish xenograft tumor model. The results from this study elaborated that sEV-TGF-β1 intercellular transfer contributes to adriamycin resistance in BCa. Citation Format: Zhi Xu, JInhai Tang. Small extracellular vesicle-mediated intercellular TGF-β1 transferring promotes adriamycin-resistant transmission in breast cancer cells [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-27.

S-Bridged pyranonaphthoquinone dimers, naquihexcins A and B (1 and 2), together with a related analogue (−)-BE-52440A (3) were obtained from the culture of a sponge-derived Streptomyces sp. HDN-10-293. Naquihexcin A (1) bears a rare unsaturated hexuronic acid moiety, and (−)-BE-52440A (3) has been discovered from natural resources. Compound 3 showed cytotoxicity against NB4 and HL-60 cells, while 1 could inhibit the proliferation of the adriamycin resistant human breast cancer cell line MCF-7 ADM.

We have developed an homogeneous assay to measure the uptake and efflux of [14C]adriamycin (doxorubicin hydrochloride) in human squamous lung carcinoma cells (SKMES-1), using 96 well scintillating microplates. The assay was also used to examine the effect of inhibitors of multidrug resistance in adriamycin resistant cells (SKMES-1/ADR). The effect of adriamycin on cell growth and viability was examined by continuous monitoring of the uptake of [14C]thymidine. The non-invasive nature of these assays, and the ease of use of the microplates, suggests a role in screens for, and characterisation of, novel chemotherapeutic or chemosensitizing agents.

Adriamycin resistant cells were obtained from low dosage treated BABL/c mice inoculated with S-180 cells. Resistance of these cells for adriamycin was 66-fold more than their parental cells. The resistance for a typical DNA topoisomerase II inhibitor VP16 (Etoposide) was increased 9 times. Overexpression of multidrug resistant gene (MDR gene) products, P-glycoproteins (P-l 70), was also demonstrated by immunohistochemistry. Furthermore, the ability of the resistant cells to reduce net cellular drug accumulation measured by flow fluorescence cytometry was 89-fold higher than their parental cells. These results support the hypothesis that the resistance of S-180R cells to adriamycin was mainly due to the overexpression of P-glycoproteins. The S- 180R cells will be useful to select drugs or some other therapeutic strategies to overcome multidrug resistancein vivo.

The synthesis and pharmacological evaluation of 7-O-(4-O-acetyl-3-iodo-2, 3, 6-trideoxy-α-L-arabino-hexopy-ranosyl)daunomycinone and 7-O-(3-chloro-2, 3, 6-trideoxy-4-O-propanoyl-α-L-lyxo-hexopyranosyl)daunomycinone are described. Their cytotoxic activity was evaluated against normal and resistant cell lines. Both compounds exhibited activity against the adriamycin resistant cell line KB-A1. These results support the hypothesis that the increased lipophilicity of the sugar part of anthracyclines is associated with their ability to overcome multidrug resistance (MDR).

A novel class of molecules with structure N-[3-(heteroaryl)propyl]-6-methoxynaphthalene-2-carboxamides 8-13 were synthesized by condensing 6-methoxy-2-naphthoyl chloride 1 with 3-(heteroaryl)propyl amines 2-7. Compounds 8-12 were evaluated in vitro, in P388 murine lymphocytic leukemia cell line (P388) using SRB assay for cytotoxicity and in adriamycin resistant P388 murine lymphocytic leukemia cell line (P388/ADR) using MTT assay for resistant reversal activity. Compounds 8-12 were non-toxic at lower dose of 20 microg/ml, and effectively reversed adriamycin resistance. However, at higher doses (40, 80 microg/ml) they showed significant cytotxicity and hence reversal potency was not determined at these concentrations.

Pharmaceutical Research, 22 (3), ISSN:0724-8741, ISSN:1573-904X

The preparation and cytotoxic activity of 4'-azido-3'-bromo-3'-deamino-4'-deoxydaunorubicin is described. The new compound was found to be less active in vitro than adriamycin against L1210 and the sensitive cell lines KB-3-1 and MES-SA, but retained interesting cytotoxicity against the adriamycin resistant subline KB-A1 and the multidrug resistant MES-SA/Dx5 subline.

Taxanes were developed as third-generation anticancer agents following methotrexate and adriamycin, two major chemotherapeutic agents for breast cancer. These agents have been studied to confirm antitumor effects in anthracycline-resistant patients and patients with liver metastasis. In this study, we examined the usefulness of taxanes, especially docetaxel, in chemotherapy for breast cancer by reviewing results in Japan and other countries. In a late phase II clinical study in Japan, the administration of 60 mg/m(2) /hr/3-4w of docetaxel (DOC) reduced tumor size in 50.4% of patients. In 6% of these patients, complete response (CR) was achieved. The duration of response was 14.7 weeks. Thirty-five percent of 26 primary adriamycin(ADM)-resistant patients responded to DOC treatment (CR:4.0%).

14050 Background: We evaluated whether combination of lapatinib, a dual tyrosine kinase inhibitor against EGFR and HER2, and fulvestrant, a full estrogen receptor antagonist, is superior in EGFR and HER2 overexpressing and non-overexpressing breast cancer cell lines regarding cell growth inhibition and effects on the protein expression level on special proteins such as PDK1 and ERK1/2. Methods: MTT assay and western blot analysis were performed in the different breast cancer cell lines BT474, T47D, MCF-7 and Adriamycin resistant MCF7 cells. Incubation time was 72h. Concentration of both agents in western blot: 1x10exp-7M, in MTT assay 10exp-11M to 10exp-5M. Results: MTT assay showed a significant stronger proliferation inhibition by lapatinib and fulvestrant in BT474 cells and non- overexpressing T47D cells at a concentration of 10E-7M compared to single agent treatment. By western blot analysis, we found a synergistic downregulation of PDK1 in the combination treatment both in BT474 and AR MCF7 cells, whereas not in T47D cells. In MCF7 cells a downregulation of p-PDK1 was observed after treatment with fulvestrant alone as well as lapatinib plus fulvestrant. Regarding ERK1/2, a synergistic downregulation could be observed in AR MCF7 cells. A downregulation of a p-ERK was detected in MCF-7 cells after treatment with lapatinib, fulvestrant or both. Conclusion: A synergistic action of lapatinib and fulvestrant was observed in all 4 cell lines despite their different receptor status regarding EGFR, HER2 and ER alpha. Shadeo et al. (2005) showed different copy number profiles in these breast cancer cell lines regarding the examined pathways. We could show by western blot analysis that the combination treatment had inhibitory effect on these cell lines according to their individual up-regulated pathways. Altogether, this suggests that the combination is a promising treatment not only in EGFR and HER2 over-expressing breast cancer and that treatment effect is also dependent on up-regulated pathways more likely than receptor status. No significant financial relationships to disclose.

The morphological changes associated with Adriamycin resistance in a human leukemic cell line have been investigated by image analysis. An Adriamycin-resistant subline of the human erythroleukemic K562 cell line has been established. Three sets of cells have been analysed: sensitive cells, resistant cells cultured in the continuous presence of Adriamycin, and resistant cells cultured without the drug. Image analysis shows that Adriamycin-resistant K562 cells display significant morphological changes as compared with sensitive cells, at both the nuclear and cytoplasmic levels. These changes make it possible to separate sensitive and resistant cells automatically and with a classification accuracy of 76% and only four cytological parameters. Image analysis may therefore offer an interesting tool for studying drug resistance in leukemic cells, from both an experimental and a clinical point of view.

Cell surface alteration was studied in a subline of murine lymphocytic leukaemia resistant to the broad-spectrum anticancer agent adriamycin (P388/ADR) employing concanavalin A(Con A)-induced agglutination and rearrangement of lectin receptors. Con A induced more agglutination of P388/ADR when compared to the drug-sensitive parental cell line (P388/S). Studies on the redistribution of Con A and Ricinus communis agglutinin-I revealed a high percentage of P388/ADR showing internalized fluorescence, while a majority of P388/S displayed a uniform distribution of fluorescence on the cell surface.

By treatment of the sarcoma 180 (ascites) with adriamycin over 30 passages in NMRI mice, an adriamycin-resistant tumor cell line was developed. The resistance could be detected both in animal experiments and in the short-term test. In spite of treatment of the sarcoma 180 with triaziquone over 50 passages, no resistance could be detected against triaziquone either in the in vitro test or in animal experiments. The necessary criterion for a pretherapeutic test of sensitivity or resistance--a good correlation between in vivo and in vitro results--was fulfilled in all experiments carried out.

Cell surface modification was studied in a subline of murine leukemia resistant to adriamycin (P388/ADR). Lectin-induced agglutination was used as a probe. Agglutination was studied using two plant lectins, wheat germ agglutinin (WGA) and Ricinus communis agglutinin-I (RCA-I). A 7-fold higher amount of WGA and 14-fold higher amount of RCA-I were required to bring about minimum agglutination of P388/S as compared to P388/ADR. The present studies clearly indicate a change in the plasma membrane of P388/ADR cells.

Total intracellular and DNA-associated uptake of Adriamycin (ADR) was studied in V79 Chinese hamster cells and in a derived subline which is resistant to ADR killing. For both sublines, uptake of ADR was dependent on cell density with greater uptake seen with less dense cultures. Drug uptake was markedly less in the ADR-resistant cells compared to parent V79 cells. These results suggest that the resistance observed is in large part due to membrane changes that result in decreased drug uptake.