PMID- 24625970
OWN - NLM
STAT- MEDLINE
DCOM- 20141021
LR  - 20211021
IS  - 2041-4889 (Electronic)
VI  - 5
IP  - 3
DP  - 2014 Mar 13
TI  - Harnessing the lysosome-dependent antitumor activity of phenothiazines in human 
      small cell lung cancer.
PG  - e1111
LID - 10.1038/cddis.2014.56 [doi]
AB  - Phenothiazines are a family of heterocyclic compounds whose clinical utility 
      includes treatment of psychiatric disorders as well as chemotherapy-induced 
      emesis. Various studies have demonstrated that these compounds possess cytotoxic 
      activities in tumor cell lines of different origin. However, there is 
      considerable confusion regarding the molecular basis of phenothiazine-induced 
      cell death. Lung cancer (LC) remains one of the most prevalent and deadly 
      malignancies worldwide despite considerable efforts in the development of 
      treatment strategies, especially new targeted therapies. In this work, we 
      evaluated the potential utility of phenothiazines in human LC. We show that 
      phenothiazines as single treatment decreased cell viability and induced cell 
      death preferentially in small cell lung carcinoma (SCLC) over non small cell lung 
      carcinoma (NSCLC) cell lines. Sensitivity to phenothiazines was not correlated 
      with induction of apoptosis but due to phenothiazine-induced lysosomal 
      dysfunction. Interestingly, the higher susceptibility of SCLC cells to 
      phenothiazine-induced cell death correlated with an intrinsically lower buffer 
      capacity in response to disruption of lysosomal homeostasis. Importantly, this 
      effect in SCLC occurred despite mutation in p53 and was not influenced by 
      intrinsic sensitivity/resistance toward conventional chemotherapeutic agents. Our 
      data thus uncovered a novel context-dependent activity of phenothiazines in SCLC 
      and suggest that phenothiazines could be considered as a treatment regimen of 
      this disease, however, extended cell line analyses as well as in vivo studies are 
      needed to make such conclusion.
FAU - Zong, D
AU  - Zong D
AD  - Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska 
      Institutet, Stockholm, Sweden.
FAU - Zielinska-Chomej, K
AU  - Zielinska-Chomej K
AD  - Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska 
      Institutet, Stockholm, Sweden.
FAU - Juntti, T
AU  - Juntti T
AD  - Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska 
      Institutet, Stockholm, Sweden.
FAU - Mork, B
AU  - Mork B
AD  - Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska 
      Institutet, Stockholm, Sweden.
FAU - Lewensohn, R
AU  - Lewensohn R
AD  - Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska 
      Institutet, Stockholm, Sweden.
FAU - Haag, P
AU  - Haag P
AD  - Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska 
      Institutet, Stockholm, Sweden.
FAU - Viktorsson, K
AU  - Viktorsson K
AD  - Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska 
      Institutet, Stockholm, Sweden.
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140313
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Phenothiazines)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Carcinoma, Non-Small-Cell Lung/genetics/*metabolism/pathology
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Resistance, Neoplasm
MH  - Humans
MH  - Lung Neoplasms/genetics/*metabolism/pathology
MH  - Lysosomes/*drug effects/metabolism/pathology
MH  - Mutation
MH  - Phenothiazines/*pharmacology
MH  - Small Cell Lung Carcinoma/genetics/*metabolism/pathology
MH  - Time Factors
MH  - Tumor Suppressor Protein p53/genetics/metabolism
PMC - PMC3973193
EDAT- 2014/03/15 06:00
MHDA- 2014/10/22 06:00
PMCR- 2014/03/01
CRDT- 2014/03/15 06:00
PHST- 2013/09/24 00:00 [received]
PHST- 2013/12/23 00:00 [revised]
PHST- 2014/01/14 00:00 [accepted]
PHST- 2014/03/15 06:00 [entrez]
PHST- 2014/03/15 06:00 [pubmed]
PHST- 2014/10/22 06:00 [medline]
PHST- 2014/03/01 00:00 [pmc-release]
AID - cddis201456 [pii]
AID - 10.1038/cddis.2014.56 [doi]
PST - epublish
SO  - Cell Death Dis. 2014 Mar 13;5(3):e1111. doi: 10.1038/cddis.2014.56.