Induction of Apoptosis and Autophagy in Human Pancreatic Cancer Cells by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin

Abstract

Pancreatic cancer is amongst the deadliest cancers in the world. It is associated with poor prognosis, is notorious for developing chemoresistance, and very few approved chemotherapeutics are available to treat this disease. The natural compound pancratistatin (PST) has shown to effectively induce cytotoxicity selectively in numerous cancer cell types. However, it is present in only minute quantities in its natural source and many complications have burdened its chemical synthesis. We have overcome these bottlenecks by synthesizing a C-1 acetoxymethyl analogue of 7-deoxypancratistatin, JC-TH-acetate-4 (JCTH-4), which we have shown to have similar selective anti-cancer activity to that of PST. In this report, we show JCTH-4 to be a potent chemotherapeutic against pancreatic cancer cells (BxPC-3, PANC-1). It induced apoptosis selectively in BxPC-3 and PANC-1 cells by targeting the mitochondria; it dissipated mitochondrial membrane potential, caused release of apoptogenic factors, and in isolated mitochondria, increased the generation of reactive oxygen species. Furthermore, JCTH-4 selectively induced autophagy in pancreatic cancer cells while normal human fetal fibroblasts were markedly less sensitive to JCTH-4 insult. Altogether, this study outlines JCTH-4 as a potentially safe and effective chemotherapeutic agent in treating notoriously chemoresistant pancreatic cancer.

Spiclomazine Induces Apoptosis Associated with the Suppression of Cell Viability, Migration and Invasion in Pancreatic Carcinoma Cells

“…Presently, a wide variety of compounds have been discovered to perform their pharmacological effects against some diseases through inducing apoptosis in various tumor cells of human origin [26]–[28]. As of now, some modes of action induced by therapeutic drugs in the apoptotic pathways have been delineated [29]–[34]. Herein, we were interested in testing the effect of spiclomazine on the apoptosis-inducing of CFPAC-1 and MIA PaCa-2 in vitro .…”

Phenanthridone Alkaloids of the Amaryllidaceae as Activators of the Apoptosis-related Proteolytic Enzymes, Caspases

“…To this extent, compound 2 was able to decrease MMP, increase levels of ROS and cytochrome c in isolated mitochondria and induce autophagic effects in both cell lines [27]. As observed in the Saos-2, BxPC-3 and PANC-1 cells above [23,26], the caspase inhibitor Z-VAD-FMK (at both 25 and 50 μM) could not protect HCT116 cells from the apoptotic onslaught of compound 2 (1 μM) [27]. This confirmed the action of this alkaloid to be at the stage of mitochondrial destabilization, upstream of executioner caspase activation, which in turn caused the release of various apoptogenic factors involved in both caspase dependent and independent pathways of apoptotic induction [27].…”

“…Caspase signaling upstream of mitochondrial membrane permeabilization, independent of mitochondria, is thus not vital for the induction of apoptosis by 2 thereby vindicating the possibility of a mitochondrial target for this alkaloid [23]. Further studies of phenanthridone (2) showed it to be very active against the pancreatic cancer cells BxPC-3 and PANC-1 at dosages of 0.1 to 2 μM [26]. It induced apoptosis selectively in these cells by targeting the mitochondria where it dissipated MMP, increased the generation of ROS and caused the release of apoptogenic factors [26].…”

“…Further studies of phenanthridone (2) showed it to be very active against the pancreatic cancer cells BxPC-3 and PANC-1 at dosages of 0.1 to 2 μM [26]. It induced apoptosis selectively in these cells by targeting the mitochondria where it dissipated MMP, increased the generation of ROS and caused the release of apoptogenic factors [26]. Phenanthridone (2) (1 M) caused the release of AIF and cytochrome c from the mitochondria of BxPC-3 cells, and diminished the retention of Endo G in PANC-1 mitochondria [26].…”

“…It induced apoptosis selectively in these cells by targeting the mitochondria where it dissipated MMP, increased the generation of ROS and caused the release of apoptogenic factors [26]. Phenanthridone (2) (1 M) caused the release of AIF and cytochrome c from the mitochondria of BxPC-3 cells, and diminished the retention of Endo G in PANC-1 mitochondria [26]. Z-VAD-FMK was unable to protect BxPC-3 cells from the effects of phenanthridone (2), again indicating a caspase-independent mode of action [26].…”