Cellular effects of the microtubule-targeting agent peloruside A in hypoxia-conditioned colorectal carcinoma cells

Peloruside A-Induced Cell Death in Hypoxia Is p53 Dependent in HCT116 Colorectal Cancer Cells

“…Our previous study revealed that hypoxia (1% oxygen) preconditioning does not affect the sensitivity of HCT116 cells to peloruside A (PLA), an MSA from the marine sponge Mycale hentscheli . Although PLA is less cytotoxic than paclitaxel in normoxia, the ability of PLA to induce mitotic arrest of cervical cancer HeLa cells and apoptosis in HCT116 cells is not altered by hypoxia conditioning of cells.…”

“…Additionally, PLA induces p53 in breast cancer MCF-7 cells and activates the expression of p21 in PLA-sensitive and PLA-resistant ovarian 1A9 cancer cells . Similarly, HIF-1α-expressing HCT116 cells show an induction of p53 following PLA treatment . Given the relation between HIF-1α and p53, and since the expression of p21 is regulated by both p53 and HIF-1α, we sought to determine if the effects of PLA in hypoxic (1% oxygen) cells are p53- and/or p21-dependent.…”

“…Unlike our previous study in which hypoxia-preconditioned cells were treated with drugs in normoxia, in the present study, HCT116 cells, preconditioned to hypoxia for 4 h, were treated with PLA under hypoxic conditions for a further 16–32 h. The reason for this preconditioning was to allow resistance mechanisms to develop and be consistent with our earlier paper . We first determined the effect of hypoxia alone on the proliferation of cells cultured under hypoxic conditions for 0–32 h using a crystal violet staining (CVS) cell proliferation assay .…”

“…However, there was no apparent cell death in PLA-untreated WT or p53-deficient cells due to hypoxia in our study (Figure C–E), although the increase in the percentage of cell death in p21 –/– cell cultures after 16 h hypoxia (Figure C) is noteworthy. We have previously shown that PLA activates caspases and cell death by apoptosis in hypoxia-preconditioned WT HCT116 cells under normoxic conditions . Similarly, compared to the untreated cells, there was a dose- and time-dependent increase in the percentage of cell death following PLA treatment of all four cell lines under hypoxia (Figure C–E).…”