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Harnessing the lysosome-dependent antitumor activity of phenothiazines in human small cell lung cancer.

Zong D, Zielinska-Chomej K, Juntti T, Mörk B, Lewensohn R, Hååg P, Viktorsson K - Cell Death Dis (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
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.

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Related in: MedlinePlus

A working model for the lysosome-dependent usage of phenothiazines in human LC. Chemical structure common to all phenothiazines followed by hypothetical mechanisms of actions in LC is presented. Lower lysosomal mass and buffer capacity of the SCLC cells results in perturbations of lysosomal functions causing cell death while NSCLC cells with higher lysosomal mass and buffer capacity survive
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fig7: A working model for the lysosome-dependent usage of phenothiazines in human LC. Chemical structure common to all phenothiazines followed by hypothetical mechanisms of actions in LC is presented. Lower lysosomal mass and buffer capacity of the SCLC cells results in perturbations of lysosomal functions causing cell death while NSCLC cells with higher lysosomal mass and buffer capacity survive

Mentions: In summary, the present work uncovered a novel activity of phenothiazines as agents capable of inhibiting survival and inducing cell death in human SCLC (Figure 7), a tumor type that is notoriously difficult to treat with conventional CT because of its ability to rapidly acquire resistance. Moreover, we provide evidence showing that phenothiazine-induced disruption of lysosomal functions is critically required for phenothiazine-induced cell death effects, with SCLC especially susceptible because of their inherently low lysosomal number and/or pH. Finally, our data suggest that analysis of intrinsic lysosomal functions may identify SCLC cases that are most likely to respond to phenothiazine-based regimens, however, extended cell line analyses as well as in vivo studies are needed to formulate such conclusion. On the basis of these findings, we conclude that phenothiazines are suitable lead compounds for further development of lysosome-targeted treatment to combat SCLC and which merit further analysis for antitumor efficacy in patient-derived xenograft models and/or genetically modified mice models of SCLC.


Harnessing the lysosome-dependent antitumor activity of phenothiazines in human small cell lung cancer.

Zong D, Zielinska-Chomej K, Juntti T, Mörk B, Lewensohn R, Hååg P, Viktorsson K - Cell Death Dis (2014)

A working model for the lysosome-dependent usage of phenothiazines in human LC. Chemical structure common to all phenothiazines followed by hypothetical mechanisms of actions in LC is presented. Lower lysosomal mass and buffer capacity of the SCLC cells results in perturbations of lysosomal functions causing cell death while NSCLC cells with higher lysosomal mass and buffer capacity survive
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3973193&req=5

fig7: A working model for the lysosome-dependent usage of phenothiazines in human LC. Chemical structure common to all phenothiazines followed by hypothetical mechanisms of actions in LC is presented. Lower lysosomal mass and buffer capacity of the SCLC cells results in perturbations of lysosomal functions causing cell death while NSCLC cells with higher lysosomal mass and buffer capacity survive
Mentions: In summary, the present work uncovered a novel activity of phenothiazines as agents capable of inhibiting survival and inducing cell death in human SCLC (Figure 7), a tumor type that is notoriously difficult to treat with conventional CT because of its ability to rapidly acquire resistance. Moreover, we provide evidence showing that phenothiazine-induced disruption of lysosomal functions is critically required for phenothiazine-induced cell death effects, with SCLC especially susceptible because of their inherently low lysosomal number and/or pH. Finally, our data suggest that analysis of intrinsic lysosomal functions may identify SCLC cases that are most likely to respond to phenothiazine-based regimens, however, extended cell line analyses as well as in vivo studies are needed to formulate such conclusion. On the basis of these findings, we conclude that phenothiazines are suitable lead compounds for further development of lysosome-targeted treatment to combat SCLC and which merit further analysis for antitumor efficacy in patient-derived xenograft models and/or genetically modified mice models of SCLC.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology-Pathology, Karolinska Biomics Center, Karolinska Institutet, Stockholm, Sweden.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus