Penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis

Ranjan, Alok; Srivastava, Sanjay

doi:10.1038/srep26165

Cited by 52 publications

(72 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The cells were collected after treatment with penfluridol and processed for western blot analysis as described by us before. 11 …”

Section: Silencing Of Chopmentioning

confidence: 99%

“…The results of this experiment have been published. 11 A part of tumors from control-and penfluridol-treated mice from this experiment was used to perform western blot analysis in this study.…”

Section: Subcutaneous Implantation Of Pancreatic Tumormentioning

confidence: 99%

“…Tumor growth curve in control and penfluridol-treated group obtained from this experiment has been published. 11 A part of snapfrozen orthotopic pancreatic tumor samples from control and penfluridol-treated group from this experiment was used to perform western blot analysis for ER stress markers in this study.…”

Section: Orthotopic Tumor Modelmentioning

confidence: 99%

“…Tumor volume was measured twice a week till day 27 using vernier caliper as described by us before. 11,17 Mice were humanely sacrificed and tumors were removed. The results of this experiment have been published.…”

Section: Subcutaneous Implantation Of Pancreatic Tumormentioning

confidence: 99%

“…10 Recently, we have demonstrated that penfluridol, an antipsychotic drug, suppresses pancreatic tumor growth by autophagy-mediated apoptosis. 11 However, the mechanism leading to penfluridol-induced autophagy in pancreatic cancer remains unknown.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer

et al. 2017

Self Cite

View full text Add to dashboard Cite

Pancreatic cancer is one of the most aggressive and difficult to treat cancers. Experimental and clinical evidence suggests that high basal state autophagy in pancreatic tumors could induce resistance to chemotherapy. Recently, we have demonstrated that penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis both in vitro and in vivo; however, the mechanism of autophagy induction by penfluridol was not clear. Several studies have established that endoplasmic reticulum stress could lead to autophagy and inhibit tumor progression. In this study, we demonstrated that penfluridol induced endoplasmic reticulum stress in BxPC-3, AsPC-1, and Panc-1 pancreatic cancer cell lines as indicated by upregulation of endoplasmic reticulum stress markers such as binding protein (BIP), C/EBP homologous protein (CHOP) and inositol requiring 1α (IRE1α) after treatment with penfluridol in a concentration-dependent manner. Inhibiting endoplasmic reticulum stress by pretreatment with pharmacological inhibitors such as sodium phenylbutyrate and mithramycin or by silencing CHOP using CHOP small interfering RNA, blocked penfluridol-induced autophagy. These results clearly indicate that penfluridol-induced endoplasmic reticulum stress lead to autophagy in our model. Western blot analysis of subcutaneously implanted AsPC-1 and BxPC-3 tumors as well as orthotopically implanted Panc-1 tumors demonstrated upregulation of BIP, CHOP, and IRE1α expression in the tumor lysates from penfluridol-treated mice as compared to tumors from control mice. Altogether, our study establishes that penfluridol-induced endoplasmic reticulum stress leads to autophagy resulting in reduced pancreatic tumor growth. Our study opens a new therapeutic target for advanced chemotherapies against pancreatic cancer.

show abstract

“…The cells were collected after treatment with penfluridol and processed for western blot analysis as described by us before. 11 …”

Section: Silencing Of Chopmentioning

confidence: 99%

Section: Subcutaneous Implantation Of Pancreatic Tumormentioning

confidence: 99%

Section: Orthotopic Tumor Modelmentioning

confidence: 99%

Section: Subcutaneous Implantation Of Pancreatic Tumormentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

Cationic amphiphilic drugs as potential anticancer therapy for bladder cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

RETRACTED: Penfluridol triggers mitochondrial‐mediated apoptosis and suppresses glycolysis in colorectal cancer cells through down‐regulating hexokinase‐2

Wang

Zhang

et al. 2020

The Anatomical Record

View full text Add to dashboard Cite

Penfluridol, a commonly used antipsychotic agent in a clinical setting, exhibits potential anticancer properties against various human malignancies. Here, we investigated the effect of penfluridol on the biological behavior of colorectal cancer (CRC) cells. Cell viability and clonogenic potential were detected by the cell counting kit‐8 and colony formation assay. The cell apoptosis and cell cycle distribution were quantified through flow cytometry. Caspase‐3 activity, glucose consumption, lactate production, and intracellular ATP levels were evaluated using the corresponding commercial detection kits. The protein levels of related genes were detected through western blotting. Mitochondrial membrane potential was detected using JC‐1 staining. A CRC xenograft tumor model was used to validate the antitumor activity of penfluridol in vivo. Penfluridol reduced cell survival and promoted apoptotic cell death effectively through the mitochondria‐mediated intrinsic pathway in a dose‐dependent manner. Furthermore, the process of glycolysis in HCT‐116 and HT‐29 cells was inhibited upon penfluridol treatment, as evidenced by the decrease in glucose consumption, lactate production, and intracellular ATP levels. Further mechanistic studies revealed that penfluridol influenced cell apoptosis and glycolysis in CRC cells by downregulating hexokinase‐2 (HK‐2). The proapoptotic effect and glycolytic inhibition‐induced by penfluridol were effectively reversed by HK‐2 overexpression. Consistent with in vitro results, penfluridol could also suppress tumor growth and trigger apoptosis in vivo. Penfluridol triggers mitochondrial‐mediated apoptosis and induces glycolysis inhibition via modulating HK‐2 in CRC and provides a theoretical basis to support penfluridol as a repurposed drug for CRC patients.

show abstract

Penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis

Cited by 52 publications

References 33 publications

Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer

Penfluridol induces endoplasmic reticulum stress leading to autophagy in pancreatic cancer

Cationic amphiphilic drugs as potential anticancer therapy for bladder cancer

RETRACTED: Penfluridol triggers mitochondrial‐mediated apoptosis and suppresses glycolysis in colorectal cancer cells through down‐regulating hexokinase‐2

Contact Info

Product

Resources

About