title: Therapeutic targeting of replicative immortality.
abstract: One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed "senescence," can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells' heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy.
authors: Life Sciences Division, Lawrence Berkeley National Lab, Berkeley, CA, United States. Electronic address: p_yaswen@lbl.gov.
authors: Paul
authors: P
authors: Yaswen
authors: Children's Cancer Institute Australia, Kensington, New South Wales, Australia. Electronic address: k.mackenzie@unsw.edu.au.
authors: Karen L
authors: KL
authors: MacKenzie
authors: University of Glasgow, Glasgow, United Kingdom. Electronic address: nicol.keith@glasgow.ac.uk.
authors: W Nicol
authors: WN
authors: Keith
authors: Old Dominion University, Norfolk, VA, United States. Electronic address: hentoshp@hotmail.com.
authors: Patricia
authors: P
authors: Hentosh
authors: Université de Montréal, Montréal, QC, Canada. Electronic address: rodierf@mac.com.
authors: Francis
authors: F
authors: Rodier
authors: Washington State University College of Pharmacy, Pullman, WA, United States. Electronic address: jiyue.zhu@wsu.edu.
authors: Jiyue
authors: J
authors: Zhu
authors: University of California Berkeley, Berkeley, CA, United States. Electronic address: glfire@berkeley.edu.
authors: Gary L
authors: GL
authors: Firestone
authors: Biodonostia Institute, Gipuzkoa, Spain. Electronic address: ander.matheu@biodonostia.org.
authors: Ander
authors: A
authors: Matheu
authors: Instituto de Biomedicina de Sevilla, HUVR, Consejo Superior de Investigaciones Cientificas, Universdad de Sevilla, Seville, Spain. Electronic address: acarnero@us.es.
authors: Amancio
authors: A
authors: Carnero
authors: University of Glasgow, Glasgow, United Kingdom. Electronic address: Alan.Bilsland@glasgow.ac.uk.
authors: Alan
authors: A
authors: Bilsland
authors: Sentara Healthcare, Norfolk, VA, United States. Electronic address: trsundin@sentara.com.
authors: Tabetha
authors: T
authors: Sundin
authors: Nara Medical University, Kashihara, Nara, Japan.
authors: Kanya
authors: K
authors: Honoki
authors: Nara Medical University, Kashihara, Nara, Japan.
authors: Hiromasa
authors: H
authors: Fujii
authors: National Technical University of Athens, Athens, Greece.
authors: Alexandros G
authors: AG
authors: Georgakilas
authors: University of Florence, Florence, Italy.
authors: Amedeo
authors: A
authors: Amedei
authors: United Arab Emirates University, Al Ain, United Arab Emirates; Cairo University, Cairo, Egypt.
authors: Amr
authors: A
authors: Amin
authors: University of Illinois at Urbana Champaign, Champaign, IL, United States.
authors: Bill
authors: B
authors: Helferich
authors: Creighton University, Omaha, NE, United States.
authors: Chandra S
authors: CS
authors: Boosani
authors: SASTRA University, Thanjavur, Tamil Nadu, India.
authors: Gunjan
authors: G
authors: Guha
authors: The University of Rome Tor Vergata, Rome, Italy.
authors: Maria Rosa
authors: MR
authors: Ciriolo
authors: Ovarian and Prostate Cancer Research Trust, Guildford, Surrey, United Kingdom.
authors: Sophie
authors: S
authors: Chen
authors: Purdue University, West Lafayette, IN, United States.
authors: Sulma I
authors: SI
authors: Mohammed
authors: Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States.
authors: Asfar S
authors: AS
authors: Azmi
authors: SASTRA University, Thanjavur, Tamil Nadu, India.
authors: Dipita
authors: D
authors: Bhakta
authors: New York Medical College, Valhalla, NY, United States.
authors: Dorota
authors: D
authors: Halicka
authors: University of Florence, Florence, Italy.
authors: Elena
authors: E
authors: Niccolai
authors: The University of Rome Tor Vergata, Rome, Italy.
authors: Katia
authors: K
authors: Aquilano
authors: United Arab Emirates University, Al Ain, United Arab Emirates; Cairo University, Cairo, Egypt.
authors: S Salman
authors: SS
authors: Ashraf
authors: Mayo Clinic, Rochester, MN, United States.
authors: Somaira
authors: S
authors: Nowsheen
authors: University of Illinois at Urbana Champaign, Champaign, IL, United States.
authors: Xujuan
authors: X
authors: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D042822:Genomic Instability / Q000187:drug effects; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D019098:Telomerase / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D019869:Phosphatidylinositol 3-Kinases; D019098:Telomerase
keywords: Oncogenic stress; Senescence; Telomerase; p53; pRB