PubMed · 4156524
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L Love. 1974. The view box.. https://pubmed.ncbi.nlm.nih.gov/4156524/
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The G12 subfamily of heterotrimeric G proteins, comprised of the alpha-subunits Galpha12 and Galpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. In an attempt to elucidate specific roles of this subfamily in cell regulation, we sought to identify molecular targets of Galpha12. Here we show a specific interaction between the G12 subfamily and the cytoplasmic tails of several members of the cadherin family of cell-surface adhesion proteins. Galpha12 or Galpha13 binding causes dissociation of the transcriptional activator beta-catenin from cadherins. Furthermore, in cells lacking the adenomatous polyposis coli protein required for beta-catenin degradation, expression of mutationally activated Galpha12 or Galpha13 causes an increase in beta-catenin-mediated transcriptional activation. These findings provide a potential molecular mechanism for the previously reported cellular transforming ability of the G12 subfamily and reveal a link between heterotrimeric G proteins and cellular processes controlling growth and differentiation.
A new dihydrofolate reductase inhibitor, edatrexate (EDX), and the microtubule polymerization promotor, taxol (TXL) or taxotere (TXT), each have significant therapeutic activity against human breast cancer in clinical trials. Since they also have distinctly different mechanisms of actions and have mainly non-overlapping toxicities, they may be effective in combination in the treatment of this disorder. Schedule-dependent interactions between these taxanes and EDX against human breast adenocarcinoma cells (SK-Br-3) were quantitatively assessed in vitro to determine whether these interactions are synergistic or antagonistic. SK-Br-3 cells were grown as a monolayer in 96-well microplates. The dose-effect relationships of the drugs, singly and in combination, in inhibiting the growth over a 7-day period were determined by the SRB protein staining assays. Cell cultures were exposed to drug as a 3-h pulse at either 0-3 h or 24-27 h. Synergism or antagonism at different concentrations and at different effect levels were assessed with the median effect principle and the combination index-isobologram method using computer software. These methods were selected because they take into account both the potencies and the shape of the dose-effect curves. Exposure of cells to an equimolar combination of EDX + TXL (0-3 h) resulted in synergism at high effect levels. Pretreatment of cells with EDX (0-3 h) followed by TXL (24-27 h) showed even greater synergism in inhibiting cell growth. Moderate antagonism was observed with the reverse schedule. EDX + TXT (0-3 h) was additive, but pretreatment with EDX (0-3 hr) followed by TXT (24-27 h) showed synergism. However, the reverse order showed antagonism. Studies on another breast tumor cell line, ZR-57-1, also showed the schedule of EDX (0-3 h) + TXT or TXL (24-27 h) to be more synergistic than, the other two schedules examined. These results show potent schedule-dependent synergism of the combinations of TXL or TXT with EDX, and should form a rationale for designing clinical protocols utilizing these agents particularly for the treatment of breast cancer patients.
Effective adjunctive therapies for colorectal carcinoma are clearly needed. We evaluated the cytotoxic responses in vitro of human colon carcinoma cell lines to combined modalities: 5-fluorouracil/leucovorin (5-FU/LV), carboplatin (CP), tumor necrosis factor (TNF) and hyperthermia (HTX). Cytotoxicity was evaluated in a cell proliferation assay using crystal violet staining. 5-FU/LV was administered 2-3 days before TNF and CP, followed 1 h later by HTX. These cell lines were relatively resistant to HTX alone (42 degrees C for 2 h), but were heterogeneous in their responses to various doses of the other single agents. This heterogeneity was also evident for combined modalities: the HCT-15 cell line exhibited significant supra-additivity for selected doses of CP, TNF and 5-FU/LV, which was further enhanced by hyperthermia. In contrast, the HT-29 cell line did not demonstrate a strong pattern for supra-additivity, whereas the DLD-1 cell line had an intermediate response. Thus, our results suggest one approach to develop effective and dose-sparing multimodality therapeutic regimens for colon adenocarcinoma.