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  3. Medizin - Open Access LMU - Teil 17/22 Podcast
  4. Tamoxifen enhances the cytotoxic effects of nelfinavir in breast cancer cells
Introduction: The HIV protease inhibitor nelfinavir is currently
under investigation as a new anti-cancer drug. Several studies have
shown that nelfinavir induces cell cycle arrest, endoplasmic
reticulum stress, autophagy, and apoptosis in cancer cells. In the
present article, the effect of nelfinavir on human breast cancer
cells is examined and potential combination treatments are
investigated. Methods: The effects of nelfinavir and tamoxifen on
the human breast cancer cell lines MCF7, T47 D, MDA-MB-453, and
MDA-MB-435 were tested by analysing their influence on cell
viability (via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide assay), apoptosis (annexin binding, poly(ADP-ribose)
polymerase cleavage), autophagy (autophagy marker light chain 3B
expression), endoplasmic reticulum stress (binding protein and
activating transcription factor 3 expression), and the occurrence
of oxidative stress (intracellular glutathione level). Results:
Nelfinavir induced apoptosis in all four breast cancer cell lines
tested, although the extent of autophagy and endoplasmic reticulum
stress varied among the cell lines. The concentration of nelfinavir
needed for an efficient induction of apoptosis in breast cancer
cells could be reduced from 15 mu g/ml to 6 mu g/ml when combined
with tamoxifen. At a concentration of 6 mu g/ml, tamoxifen
substantially enhanced the endoplasmic reticulum stress reaction in
those cell lines that responded to nelfinavir with binding protein
(BiP) upregulation (MCF7, T47D), and enhanced autophagy in cell
lines that responded to nelfinavir treatment with autophagy marker
light chain 3B upregulation (MDA-MB-453). Although tamoxifen has
been described to be able to induce oxidative stress at
concentrations similar to those applied in this study (6 mu g/ml),
we observed that nelfinavir but not tamoxifen reduced the
intracellular glutathione level of breast cancer cells within hours
of application by up to 32%, suggesting the induction of oxidative
stress was an early event and an additional cause of the apoptosis
induced by nelfinavir. Conclusions: The results demonstrate that
nelfinavir may be an effective drug against breast cancer and could
be combined with tamoxifen to enhance its efficacy against breast
cancer cells. Moreover, the cytotoxic effect of a tamoxifen and
nelfinavir combination was independent of the oestrogen receptor
status of the analysed breast cancer cells, suggesting a potential
benefit of a combination of these two drugs even in patients with
no hormone-responsive tumours. We therefore recommend that clinical
studies on nelfinavir with breast cancer patients should include
this drug combination to analyse the therapeutic efficacy as well
as the safety and tolerability of this potential treatment option.

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„Tamoxifen enhances the cytotoxic effects of nelfinavir in breast cancer cells“

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