Pancreatic Adenocarcinoma

Abstract

Cisplatin is an efficient anticancer agent. Cisplatin-based chemotherapy is believed to involve different signal transduction pathways, among which calpain activation has been proposed as an important factor in the induced apoptosis. In our study, based on real-time single cell analysis, we investigated the molecular involvement of calpain in cisplatin-induced apoptosis in living human lung adenocarcinoma cells. After cisplatin treatment, calpain was activated, resulting in Bid cleavage at 4-5 hr, followed by Bid translocation and cytochrome c release, leading to cell death. Calpeptin and PD150606, specific inhibitors of calpain, blocked Bid activation completely; however, cytochrome c release was delayed by more than 2 hr, which was associated with the delay of caspase-3 activation and cell death. Remarkably, calpainmediated release of cytochrome c and cell death was significantly compromised in the Bid knockdown cells. Z-IETD-fmk and Z-VDVAD-fmk were used to block the activation of caspase-8 and caspase-2, respectively; however, the progression of apoptosis were not affected, suggesting that caspase-8 and caspase-2 were not involved in this experimental model. Taken together, the data demonstrate that calpain mediated cisplatin-induced apoptosis in human lung adenocarcinoma cells through activating Bid, which then regulated the mitochondrial apoptotic pathway. The delays of cytochrome c release, caspase-3 activation and subsequent cell death by inactivating calpain or silencing Bid exclude other earlier or parallel pathways, strongly suggesting that the calpain-mediated pathway is the kinetically earliest one, which dominates the cisplatin-induced apoptosis. '

State of the art and future directions of pancreatic ductal adenocarcinoma therapy

“…Interestingly, marked inflammatory syndrome and immunosuppression are commonly observed in patients with PDAC (von Bernstorff et al, 2001). Increasing evidence suggests that oncogenic KRAS drives a paracrine and endocrine (through circulating exosomes, which are membrane vesicles of endocytic origin enclosing tumor-derived material) inflammatory and immunosuppressive program establishing a pro-tumoral immune microenvironment in PDAC primary and metastatic sites (Costa-Silva et al, 2015;Miller, 2014;Ryan et al, 2014a;Vonderheide & Bayne, 2013). Several mechanisms that are involved are summarized in Figure 2.…”

“…Risk factors: nicotine, obesity/diabetes/insulin resistance, chronic pancreatitis, and the role of inflammation PDAC risk increases with age and rarely affects individuals younger than 45; the median age at diagnosis is 71 years old (Ryan et al, 2014a). Increasing PDAC incidence in recent years may be related to population aging.…”

“…Complete surgical resection is the only treatment that can provide prolonged survival. However, due to lack of initial symptoms at early stage and high invasive potential, diagnosis is made at an advanced stage in 80% of cases, when patients already have metastases or locoregional extension (Rhim et al, 2012;Ryan, Hong, & Bardeesy, 2014a). Moreover, most patients with an apparently localized disease who may undergo a curative-intent resection will promptly develop metastatic and/or local relapses.…”

“…Several phase II and III studies have been designed as add-on benefit using various combinations of gemcitabine with other cytotoxics or targeted agents such as tyrosine kinase inhibitors and monoclonal antibodies. However, most of these doublets failed to demonstrate a superiority over gemcitabine monotherapy (Ryan et al, 2014a). The landscape of PDAC management has undergone major changes during the 5 past years with the approval of two active combinations of cytotoxics: the FOLFIRINOX (5-fluorouracil [5FU], irinotecan, and oxaliplatin) and the gemcitabine plus nab-paclitaxel regimens.…”

“…Moreover, most patients with an apparently localized disease who may undergo a curative-intent resection will promptly develop metastatic and/or local relapses. The median survival after curative resection is about 20-24 months, 9-15 months in patients with locally advanced PDAC, and 6-9 months in those with metastatic disease (Ryan et al, 2014a). Advanced PDAC remains a challenging, non-curable disease attracting attention of medical and surgical specialists, as well as pharmacologists.…”