Antitumor effect of pyrrolo-1,5-benzoxazepine-15 and its synergistic effect with Oxaliplatin and 5-FU in colorectal cancer cells

Abstract

Some compounds of a series of novel pyrrolo-1,5-benzoxa(thia)zepine, a well-known group of tubulin targeting agents, display anti-tumor effects mainly inducing cell cycle arrest and apoptosis in several human cancer models. A member of this family, pyrrolo-1,5-benzoxazepine-15 (PBOX-15), has previously shown potent pro-apoptotic activity in a variety of human tumor cell types, with minimal toxicity toward normal blood and bone marrow cells. In this study, we evaluated the PBOX-15-mediated effects in human colorectal cancer cell (CRC) lines, DLD-1 and HT-29. The compound, used at concentrations equal to or greater than 1 mM, inhibited the proliferation of human CRC cells, inducing a significant cell cycle arrest in the G2/M phase. In DLD-1 cells, treatments prolonged over 48 h triggered a strong activation of the intrinsic apoptotic pathway as indicated by activation of caspase-9, caspase-3 and PARP cleavage. Moreover, nanomolar concentrations of PBOX-15, significantly improved the oxaliplatin and 5-fluouracilinduced anti-proliferative effects in DLD1 cell line. The observed synergistic interaction of both PBOX-15/ Oxaliplatin and PBOX-15/5FU may involve activation of p38 MAPK and JNK pathway, which in turn significantly increased caspase-3 cleavage in DLD-1 cells, treated with PBOX-5/Oxaliplatin but not with PBOX-15/5FU. Moreover, PBOX-15/5FU-treated cells showed an increase in expression of the proapoptotic protein Bax. Taken together, these results show that PBOX-15 could represent a promising compound for the treatment of human CRC and a strong candidate for novel therapeutic options.

MPT0B169 and MPT0B002, New Tubulin Inhibitors, Induce Growth Inhibition, G2/M Cell Cycle Arrest, and Apoptosis in Human Colorectal Cancer Cells

“…Therefore, new anti-CRC agents are still required. Previous research indicated that a tubulin-targeting agent, pyrrolo-1,5-benzoxazepine-15, had antitumor effects in CRC cell lines [18]. We found that 0.1 µmol/L MPT0B002 and 2 µmol/L MPT0B169 had similar effects on apoptotic induction (Fig.…”

N6-Isopentenyladenosine Inhibits Colorectal Cancer and Improves Sensitivity to 5-Fluorouracil Targeting FBXW7 Tumor Suppressor

“…All reagents for cell culture, N6-isopentenyladenosine (IPA), 5-fluorouracil (5-FU) and MG132 inhibitor (dissolved in DMSO) were purchased from Sigma–Aldrich (St. Louis, MO, USA). Cell proliferation was evaluated through BrdU incorporation measurement, through a colorimetric ELISA kit (Roche Diagnostics GmbH, Mannheim, Germany), as previously described [54]. All experiments were performed in triplicate, and the relative cell proliferation was expressed as a fold change versus untreated control cells.…”

The Endocannabinoid System: A Target for Cancer Treatment

“…Interestingly, pyrrolo-1,5-benzoxazepine-15 (PBOX-15) (from 0.001 to 5 µM), a synthetic inhibitor of FAAH, demonstrated a strong antiproliferative and proapoptotic effect in CRC cell lines. Moreover, it was observed that nanomolar concentration of PBOX-15 increased the anticancer action of 5-fluouracil (5-FU) [46].…”