Acquired and innate resistance to the cancer-specific apoptosis-inducing Cytokine, mda-7/IL-24: Not insurmountable therapeutic problems

Sarkar, Devanand; Dent, Paul; Curiel, David T.; Fisher, Paul B.

doi:10.4161/cbt.7.1.5693

Cited by 9 publications

(3 citation statements)

References 44 publications

(68 reference statements)

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“…Re‐growth of such resistant cell populations annuls initially effective therapeutic measures and often leads to fatal outcomes. Cancer gene therapy may restore apoptosis in cancer cells that are resistant to conventional chemotherapeutic agents and/or radiation,7 but gene therapeutic modalities, including those using p53 and mda‐7/IL‐24, cannot be free from such a challenge 8, 9. Pataer et al 10 isolated Ad‐mda7/IL‐24‐resistant lung cancer cell lines and showed that the resistance was overcome by an inhibitor for HSP90.…”

mentioning

confidence: 99%

Down‐regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene‐therapeutic overexpression of REIC/Dkk‐3

Tanimoto

Sakaguchi

Abarzúa

et al. 2010

Intl Journal of Cancer

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We have recently shown that an adenovirus carrying REIC/Dkk‐3 (Ad‐REIC) exhibits a potent tumor‐specific cell‐killing function for various human cancers. It has also become evident that some human cancers are resistant to Ad‐REIC‐induced apoptosis. The aim of the present study was to determine the molecular mechanisms of resistance to Ad‐REIC. First, we isolated resistant clones from a human prostate cancer cell line, PC3, after repeated exposure to Ad‐REIC. Infection efficiency of the adenovirus vector and expression level of REIC/Dkk‐3 in the resistant clones were similar to those in the parental PC3 cells. By screening for alteration in levels and functional status of proteins involved in Ad‐REIC‐induced apoptosis, we found that BiP/GRP78, an ER‐residing chaperone protein, was expressed at higher levels consistently among resistant cells. Expression levels of BiP and rates of apoptosis induced by Ad‐REIC were inversely correlated. Down‐regulation of BiP with siRNA sensitized the resistant cells to Ad‐REIC in vivo as well as in culture. These results indicate that BiP is a major determinant of resistance to Ad‐REIC‐induced apoptosis. Thus BiP is useful for diagnosis of inherent and acquired resistance of cancers and also as a target molecule to overcome resistance to the gene therapeutic Ad‐REIC.

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confidence: 99%

Down‐regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene‐therapeutic overexpression of REIC/Dkk‐3

Tanimoto

Sakaguchi

Abarzúa

et al. 2010

Intl Journal of Cancer

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“…42 Thus, there is a significant level of cross talk between the PKR and the p38 MAPK signal transduction pathways. Further studies are required to identify the upstream molecules activating PKR and p38 Reproduced, by permission of the publisher, from Sarkar et al 103 morphologically distinct from apoptosis and activates a different complement of proteins, and unlike apoptosis, may occur under normal growth conditions. Autophagy is a non-selective process in which cytoplasm and organelles are (apparently) randomly assorted into the autophagosome, where they are degraded.…”

Section: Diverse Molecular and Signal Transduction Pathways Involved mentioning

confidence: 99%

“…Several approaches to achieve this objective were recently highlighted. 15 Those include (1) enhanced effectiveness of CTV adenoviruses in nude mice containing human melanoma, 100 breast, 78 colorectal 101 or therapy-resistant prostate 99 tumors in comparison with non-replicating adenoviruses Ad.mda-7, (2) augmentation of the antitumor properties of mda-7/IL-24 in combination with radiation, chemotherapy or monoclonal antibody therapy, 20,103 and (3) chemopreventive and enhanced antitumor effects of mda-7/IL-24 in combination with dietary agents that promote ROS production in pancreatic tumors. 88,89 Additionally, approaches that facilitate delivery of mda-7/IL-24 to the tumor microenvironment and tumor cells, including the use of stem cells and dendritic cells, offer promise for increasing therapeutic index of this novel cytokine.…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24

Emdad

Lebedeva

et al. 2009

Cancer Biology & Therapy

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A subtraction hybridization approach combined with a differentiation therapy model of human melanoma identified melanoma differentiation associated gene-7 (mda-7) as a gene upregulated during induction of terminal differentiation. Based on conserved structure, chromosomal location and cytokine-like properties, mda-7, has now been classified as a member of the expanding interleukin (IL)-10 gene family and designated as mda-7/IL-24. Extensive in vitro and in vivo human tumor xenograft studies confirm that mda-7/IL-24 induces apoptosis specifically in tumor cells without harming normal cells. Unique properties of mda-7/IL-24 action also include potent "bystander antitumor" activity, an ability to exert anti-angiogenic effects, immune modulating ability and a capacity to enhance the sensitivity of tumor cells to radiotherapy, chemotherapy and monoclonal antibody therapy. Very recent studies from our groups further reveal autocrine regulation and chemoprevention facilitating properties of mda-7/IL-24. Based on these remarkable antitumor attributes, mda-7/IL-24 was evaluated by intratumoral injection with a replication incompetent adenovirus expressing this gene (Ad.mda-7; INGN 241) in a phase I clinical trial in patients with metastatic melanomas and other advanced solid cancers. mda-7/IL-24 was well tolerated with significant clinical activity. This review highlights our current understanding of the molecular and biochemical basis of mda-7/IL-24 antitumor properties and highlights its potential as a viable gene-based therapy for a wide spectrum of primary and advanced cancers.

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Recombinant proteins and genomics in cancer therapy

Mehta

Özpolat

Gohil

et al. 2009

Principles of Cancer Biotherapy

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Acquired and innate resistance to the cancer-specific apoptosis-inducing Cytokine, mda-7/IL-24: Not insurmountable therapeutic problems

Cited by 9 publications

References 44 publications

Down‐regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene‐therapeutic overexpression of REIC/Dkk‐3

Down‐regulation of BiP/GRP78 sensitizes resistant prostate cancer cells to gene‐therapeutic overexpression of REIC/Dkk‐3

Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24

Recombinant proteins and genomics in cancer therapy

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