High antitumor activity of pladienolide B and its derivative in gastric cancer

Abstract

The antitumor activity of pladienolide B, a novel splicing inhibitor, against gastric cancer is totally unknown and no predictive biomarker of pladienolide B efficacy has been reported. We investigated the antitumor activity of pladienolide B and its derivative on gastric cancer cell lines and primary cultured cancer cells from carcinomatous ascites of gastric cancer patients. The effect of pladienolide B and its derivative on six gastric cancer cell lines was investigated using a MTT assay and the mean IC50 values determined to be 1.6 ± 1.2 (range, 0.6–4.0) and 1.2 ± 1.1 (range, 0.4–3.4) nM, respectively, suggesting strong antitumor activity against gastric cancer. The mean IC50 value of pladienolide B derivative against primary cultured cells from 12 gastric cancer patients was 4.9 ± 4.7 nM, indicative of high antitumor activity. When 18 SCID mice xenografted with primary cultured cells from three patients were administered the pladienolide B derivative intraperitoneally, all tumors completely disappeared within 2 weeks after treatment. Histological examination revealed a pathological complete response for all tumors. In the xenograft tumors after treatment with pladienolide B derivative, immature mRNA were detected and apoptotic cells were observed. When the expressions of cell-cycle proteins p16 and cyclin E in biopsied gastric cancer specimens were examined using immunohisctochemistry, positivities for p16 and cyclin E were significantly and marginally higher, respectively, in the low-IC50 group compared with the high-IC50 group, suggesting the possibility that they might be useful as predictive biomarkers for pladienolide B. In conclusion, pladienolide B was very active against gastric cancer via a mechanism involving splicing impairment and apoptosis induction.

Functional Genomic Screening Reveals Splicing of the EWS-FLI1 Fusion Transcript as a Vulnerability in Ewing Sarcoma

“…Several studies have assessed the cytotoxic activity of PlaB on cancer cells, reporting IC50 values ranging between ~0.5 – 8.5 nM (Kotake et al, 2007; Sato et al, 2014; Yokoi et al, 2011). The PlaB IC50 values for ES cells (at 48 h) ranged between 1.5 and 2.5 nM; values comparable with those determined for two non-fusion driven prostate cancer cell lines, PC3 and LNCaP (Figure 6A).…”

Dysregulation of the splicing machinery is directly associated to aggressiveness of prostate cancer

“…In particular, during the last years, many spliceosome inhibitors (e.g. Pladienolide-B, spliceostatin-A) have been reported and suggested as therapeutic targets in different pathologies wherein the dysregulated splicing process has been shown to be relevant [43,44]. However, while blocking the activity of the spliceosome could be less specific, targeting specific SCs and/or SFs could represent a novel and more specific approach to tackle cancer diseases in that a more reduced number but better-defined splicing events may be altered.…”

Inhibition of SF3b1 by pladienolide B evokes cycle arrest, apoptosis induction and p73 splicing in human cervical carcinoma cells

“…SF3b1 is one of the proteins that makes up the spliceosome and regulates excision of introns from pre-mRNA [17,21,34]. Interestingly, SF3b1 is also the target of pladienolide B, a natural product with antitumour activity both in cancer cell lines and in mouse xenograft models [20,22,35]. There is considerable interest in the compound as a potential chemotherapeutic, as well as a tool to study SF3b1 function in splicing and cancer development [23].…”

“…Several spliceosome modulators have already been identified [19]. One of them is pladienolide B, which directly binds splicing factor 3b1 (SF3b1) in the spliceosome [20], inhibits the splicing process in tumor cells [21][22][23]. SF3B1 result in alternative splicing events and may constitute drivers and a novel therapeutic target in cancers [24].…”