Selective in vitro and in vivo anti-tumor activity of PRLX 93936 in biological models of melanoma and ovarian cancer

Sahasrabudhe, Sudhir; Lai, Shuping; Pierce, Michael; Clemens, Christopher; Venkat, Raj Gopal; Rebentisch, Matthew; Senina, Anna V.; Becklin, Robert R.; Richards, Samuel K; Erkkila, Tracy; Robbins, Paul B.

doi:10.1200/jco.2008.26.15_suppl.14586

Cited by 5 publications

(3 citation statements)

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“…Erastin is an anti-tumor agent selective for tumor cells bearing oncogenic RAS ( 30 ). The compound binds VDAC2 but not N-terminal truncated hVDAC2 ( 182 ).…”

Section: Modulation Of Vdac1-mediated Apoptosis By Small Molecules Acmentioning

confidence: 99%

Voltage-Dependent Anion Channel 1 As an Emerging Drug Target for Novel Anti-Cancer Therapeutics

et al. 2017

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Cancer cells share several properties, high proliferation potential, reprogramed metabolism, and resistance to apoptotic cues. Acquiring these hallmarks involves changes in key oncogenes and non-oncogenes essential for cancer cell survival and prosperity, and is accompanied by the increased energy requirements of proliferating cells. Mitochondria occupy a central position in cell life and death with mitochondrial bioenergetics, biosynthesis, and signaling are critical for tumorigenesis. Voltage-dependent anion channel 1 (VDAC1) is situated in the outer mitochondrial membrane (OMM) and serving as a mitochondrial gatekeeper. VDAC1 allowing the transfer of metabolites, fatty acid ions, Ca2+, reactive oxygen species, and cholesterol across the OMM and is a key player in mitochondrial-mediate apoptosis. Moreover, VDAC1 serves as a hub protein, interacting with diverse sets of proteins from the cytosol, endoplasmic reticulum, and mitochondria that together regulate metabolic and signaling pathways. The observation that VDAC1 is over-expressed in many cancers suggests that the protein may play a pivotal role in cancer cell survival. However, VDAC1 is also important in mitochondria-mediated apoptosis, mediating release of apoptotic proteins and interacting with anti-apoptotic proteins, such as B-cell lymphoma 2 (Bcl-2), Bcl-xL, and hexokinase (HK), which are also highly expressed in many cancers. Strategically located in a “bottleneck” position, controlling metabolic homeostasis and apoptosis, VDAC1 thus represents an emerging target for anti-cancer drugs. This review presents an overview on the multi-functional mitochondrial protein VDAC1 performing several functions and interacting with distinct sets of partners to regulate both cell life and death, and highlights the importance of the protein for cancer cell survival. We address recent results related to the mechanisms of VDAC1-mediated apoptosis and the potential of associated proteins to modulate of VDAC1 activity, with the aim of developing VDAC1-based approaches. The first strategy involves modification of cell metabolism using VDAC1-specific small interfering RNA leading to inhibition of cancer cell and tumor growth and reversed oncogenic properties. The second strategy involves activation of cancer cell death using VDAC1-based peptides that prevent cell death induction by anti-apoptotic proteins. Finally, we discuss the potential therapeutic benefits of treatments and drugs leading to enhanced VDAC1 expression or targeting VDAC1 to induce apoptosis.

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“…Erastin is an anti-tumor agent selective for tumor cells bearing oncogenic RAS ( 30 ). The compound binds VDAC2 but not N-terminal truncated hVDAC2 ( 182 ).…”

Section: Modulation Of Vdac1-mediated Apoptosis By Small Molecules Acmentioning

confidence: 99%

Voltage-Dependent Anion Channel 1 As an Emerging Drug Target for Novel Anti-Cancer Therapeutics

et al. 2017

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“…It was also reported that RSL5, a compound that has increased lethality in the presence of oncogenic RAS, and erastin induced VDAC3-dependent cell death (Yang and Stockwell, 2008). Finally, the erastin analog, PRLX 93936, was found to bind VDAC2 and VDAC3 using a proteomics approach (Sahasrabudhe et al, 2008). PRLX 93936 is currently in clinical Phase I for treatment of solid tumors.…”

Section: Vdac As a Pharmacological Target For Compounds Affecting Celmentioning

confidence: 99%

VDAC1: from structure to cancer therapy

2012

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Here, we review current evidence pointing to the function of VDAC1 in cell life and death, and highlight these functions in relation to cancer. Found at the outer mitochondrial membrane, VDAC1 assumes a crucial position in the cell, controlling the metabolic cross-talk between mitochondria and the rest of the cell. Moreover, its location at the boundary between the mitochondria and the cytosol enables VDAC1 to interact with proteins that mediate and regulate the integration of mitochondrial functions with other cellular activities. As a metabolite transporter, VDAC1 contributes to the metabolic phenotype of cancer cells. This is reflected by VDAC1 over-expression in many cancer types, and by inhibition of tumor development upon silencing VDAC1 expression. Along with regulating cellular energy production and metabolism, VDAC1 is also a key protein in mitochondria-mediated apoptosis, participating in the release of apoptotic proteins and interacting with anti-apoptotic proteins. The involvement of VDAC1 in the release of apoptotic proteins located in the inter-membranal space is discussed, as is VDAC1 oligomerization as an important step in apoptosis induction. VDAC also serves as an anchor point for mitochondria-interacting proteins, some of which are also highly expressed in many cancers, such as hexokinase (HK), Bcl2, and Bcl-xL. By binding to VDAC, HK provides both metabolic benefit and apoptosis-suppressive capacity that offers the cell a proliferative advantage and increases its resistance to chemotherapy. VDAC1-based peptides that bind specifically to HK, Bcl2, or Bcl-xL abolished the cell’s abilities to bypass the apoptotic pathway. Moreover, these peptides promote cell death in a panel of genetically characterized cell lines derived from different human cancers. These and other functions point to VDAC1 as a rational target for the development of a new generation of therapeutics.

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“…The erastin analog, PRLX 93936, is a novel small molecule exhibiting therapeutic potential in an array of in vitro and in vivo tumor models, many with limited treatment options, such as melanoma. Mass spectrometry-based proteomics experiments indicate that PRLX 93936 can bind to VDAC2 and VDAC3 and is currently in clinical Phase I for treatment of solid tumors [343]. PRLX 93936 can rapidly affect ion flux, cell cycle, and mitochondrial membrane polarization, ultimately inducing caspase-dependent apoptosis.…”

Section: Ros-producing Vdac-dependent Agentsmentioning

confidence: 99%

Mitochondrial VDAC1: Function in Cell Life and Death and a Target for Cancer Therapy

Shoshan‐Barmatz¹,

Golan

2012

CMC

130

127

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Found at the outer mitochondrial membrane, the voltage-dependent anion channel, VDAC, assumes a crucial position in the cell, serving as the main interface between mitochondrial and cellular metabolisms by mediating transport of ions and metabolites. VDAC thus functions as a gatekeeper, controlling cross-talk between mitochondria and the rest of the cell. Moreover, its location at the boundary between the mitochondria and the cytosol enables VDAC to interact with proteins that mediate and regulate the integration of mitochondrial functions with other cellular activities. Here, we review current knowledge related to the roles played by VDAC in the regulation of cell life and cell death, with relation to cancer. The current concepts of altered metabolism in cancer cells are presented with specific emphasis on mitochondrial, more specifically VDAC1-bound hexokinase (HK), facilitating and promoting the high glycolytic tumor phenotype. In this respect, the up-regulation of HK expression in tumor cells and its binding to VDAC provide both a metabolic benefit and apoptosis-suppressive capacity that offers the cell a growth advantage and increases its resistance to chemotherapy. VDAC has also been recognized as a key protein in mitochondria-mediated apoptosis since it is the proposed target for the pro- and antiapoptotic Bcl-2-family of proteins, as well as due to its function in the release of apoptotic proteins located in the inter-membranal space. These and other functions point to VDAC1 as being a rational target for the development of a new generation of therapeutics.

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Selective in vitro and in vivo anti-tumor activity of PRLX 93936 in biological models of melanoma and ovarian cancer

Cited by 5 publications

References 0 publications

Voltage-Dependent Anion Channel 1 As an Emerging Drug Target for Novel Anti-Cancer Therapeutics

Voltage-Dependent Anion Channel 1 As an Emerging Drug Target for Novel Anti-Cancer Therapeutics

VDAC1: from structure to cancer therapy

Mitochondrial VDAC1: Function in Cell Life and Death and a Target for Cancer Therapy

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