Cancer-selective therapy of the future: apoptin and its mechanism of action.
Classical chemotherapy, that specifically targets rapidly proliferating cells, has been in existence for over eighty years and has proven to be fully successful in only a limited number of cancers. Thus, this review focuses on a novel, emerging approach for cancer therapy that uses alternative, and more unique features of cancer cells. This new approach facilitates the selective targeting of cancer, while sparing normal, non-transformed cells. Examples of molecules that kill cancer cells selectively are: apoptin, E4orf4, viral protein R (VpR), and Brevinin-2R. Below we focus on apoptin, a product of the third open reading frame (VP3) of the chicken anemia virus. Besides discussing apoptin's mechanism of action, we also provide concise insight into the biology of a chicken anemia virus infection. Since apoptin's cancer-selective toxicity depends on its nuclear localization, we broadly discuss mechanism(s) involved in its nuclear retention (both nuclear import and export). We also discuss recent findings on apoptin's molecular mechanism of action, with a focus on the role of Nur77 in apoptin's nucleo-cytoplasmic signaling. Finally, we compare the current findings on apoptin to the mechanism of cancer selective toxicity of E4orf4. In the 'summary' -section, besides highlighting important issues related to cancer-selective therapy, we also discuss concurrent approaches towards therapy personalization, particularly those related to the in vivo-, and real time cancer-therapy efficacy monitoring, using "lab-on-the-chip" and other emerging technologies.
Maddika
Subbareddy
S
Manitoba Institute of Cell Biology, CancerCare Manitoba, Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada.
Mendoza
Francisco J
FJ
Hauff
Kristin
K
Zamzow
Christina R
CR
Paranjothy
Ted
T
Los
Marek
M
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D036022:Capsid Proteins / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D017727:Chicken anemia virus / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy*; D019913:Nuclear Localization Signals; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D011987:Receptors, Steroid / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D014764:Viral Proteins / Q000627:therapeutic use
D000970:Antineoplastic Agents; D036022:Capsid Proteins; D004268:DNA-Binding Proteins; C121517:E4orf4 protein, adenovirus; C539821:NR4A1 protein, human; D019913:Nuclear Localization Signals; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; C091717:VP3 protein, Chicken anemia virus; D014764:Viral Proteins