components of growth regulatory machineries. By targeting highly activated growth-signaling pathways, we could not only arrest the cell growth, but also induce apoptosis in cancer cells. In fact, the oncogenic addiction paradigm postulates that cancer cells rely on just one oncogene to tip the balance between the induction of rapid cell cycle and the activation of cell cycle checkpoint that induces apoptosis [60,61,62]. Based on the oncogene addiction paradigm, targeted therapies deploy specific inhibitors of the presumed key oncogenes to treat particular cancer types [63]. The oncogenic addiction concept gained credence when Imatinib (Imatinib mesylate; commercial name Gleevec, originally STI571), a specific inhibitor of bcr-abl protein expressed in chronic myeloid leukemia (CML), successfully treated CML, achieving 5-year incident-free survival rates around 90% in most studies [64,65]. Furthermore, because inhibitory effects of Imatinib are limited to a few kinases, Imatinib had shown few side effects. Since the development of Imatinib, many more targeted drugs have been tested in clinical trials. These trials showed that many promising drugs induced rapid tumor regression with little side effects, resulting in near complete cancer remission within a few weeks. However, all too often, cancer returned within a year in treatment-resistant forms [66]. There were two ways that cancer gained resistance to the treatment: 1) mutation in the targeted oncogene and 2) gain of function mutations on the downstream effectors that constitutively activate them [67,68,69]. These mutations may have been in a small number of cells in the initial tumor mass, or they may have developed during the pro-longed treatment. Trying to remedy the situation, more targeted drugs were developed in some cases [70]. With knowledge gained through clinical trials, the oncogene addiction model was revised [71]; if we look at carcinogenesis as a step-by-step mutational process, oncogene addiction must occur after the critical oncogene activation and before the constitutively activating mutations of its down-stream effectors. Of course, during cancer development, there could be more than one oncogene addiction phase. In a later phase, cancer cells may depend on a different oncogene for cell growth and survival. Thus there may be another opportunity later on to treat cancer with a different targeted drug. Since tumors tend to be a heterogeneous mix of cells at different stages of cancer development, and if targeted drugs can only be effective at particular stages, then using a single targeted drug might only eliminate a fraction of cancer cells. Thus it will probably take multiple targeted drugs to completely eliminate most cancer types. Incoming results from the recently established Cancer Genome Atlas Project indicate that a typical solid tumor carries as many as 30–80 somatic mutations [72], suggesting difficulties faced trying to choose the right combination of targets in most cancer types. In the future, however, genome sequencing of cancer cells from individuals would enable us to identify all the somatic mutations for each individual cancer. Protein profiles of these same tumor cells could also be built. Based on the signaling pathways determined from these data, the treatment for each individual could be customized. This would be the height of personalized medicine, but even in the future, this could be an enormously expensive option. Despite the advances made in personalized medicine, we believe the ideal cancer therapy should still be the therapy that is applicable to all sorts of cancer types at many stages of development, including highly metastasized late stages of cancer. We believe the ideal cancer therapy may be possible by combining deoxyglucose with drugs targeting mitochondria for direct mechanical activation of mitochondrial outermembrane pores (MOMP). Once MOMP is activated, cytochrome c is released into 2DG-ABT Combination Therapy cytosol, activating apoptosomes, the death executioner. Thus by activating steps very close to the final step in apoptosis, we are lowering the risks of cancerous cells developing therapy-resistant mutations. There are two unique features of deoxyglucose that makes it an ideal chemotherapeutic partner. The first is the almost exclusive uptake of deoxyglucose by cancer cells (see the introduction). The second feature is that it primes cells for mitochondria-dependent apoptosis. Bak is an important component of mitochondrial outermembrane pores (MOMP). It is normally sequestered in complexes with Mcl-1 and Bcl-xL. We have shown that in cells treated with deoxyglucose, Mcl-1 dissociates from Bak, leaving only Bcl-xL to sequester Bak from forming MOMPs. Antagonists of the Bcl-2 family, such as ABT-263 and ABT-737, likely dissociate Bcl-xL from Bak, inducing apoptosis at a submicromolar concentration. Deoxyglucose-ABT-263 combination therapy was shown to be effective in eliminating cancer cells representing many different cancer types and covering different stages of development. Using human tumor cells xenografted onto nude mice, we showed that the combination therapy induced tumor regression in checkpoint defective (point mutation in p53), chemo-resistant, PTEN deleted, late stage cancer cells. In mice, the combination therapy specifically targeted tumor cells and eliminated them safely and more efficiently than 2DG or ABT alone. Even though 2DG-ABT combination therapy is still at an early stage of development as cancer therapy, it is meeting all the criteria for an all purpose- multifaceted cancer therapy. Thus we are hopeful that we may have found a simple solution to a very complex problem of treating cancer. Materials and Methods Reagents 2-Deoxy-D-glucose was purchased from Sigma (D3179). Ethyl 3-Bromopyruvate was purchased from Lancaster Chem- icals (Cat. L00582). z-VAD-fmk (benzoyl-Valinyl-Alaninyl-Aspartyl-fluoromethyl- ketone) was purchased from BD Bioscience. To stimulate death-receptor pathway in HT1080 cells, we used anti-Fas mouse antibody from MBL, clone CH-11 (CD95), 0.5 mg/ml used at 3 and 0.3 mL/ml. ABT-737 was purchased from Selleck Chemicals or provided by Abbott Laboratories, Inc. ABT-263 was purchased from Chimietech. Staurosporine, Thapsigargin, and Tunicamycin, were pur- chased from EMD Bioscience. PI3K inhibitor, LY294002, was purchased from Merk Chem- icals. Cell lines Prof. Koji Yamada, Kyushu University, generously provided MCF7, HepG2 and PANC-1. Bid KO MEF cells were a kind gift from Prof. Atan Gross, The Weizmann Institute of Science. NCI H82 cells were kind gifts from Prof. Jun Yokota, National Cancer Research Center, Tokyo. RS(4;11) cells was a kind gift from Prof. Hidemistu Kurosawa, Dept. of Pediatrics, Dokkyo Medical University, Mibu, Tochigi, Japan. Prostate cancer cell line PPC-1/PC-3 (Cytogenet Cell Genet 1993;62:183-4), and all other cells were from Sanford-Burnham Medical Research Institute. All the experiments in the article were performed using either ABT-737 or ABT-263, and then repeated using the other agent, except for the mouse xenograft work and the EM work for which only ABT-263 were used. PLoS ONE | www.plosone.org 10 September 2011 | Volume 6 | Issue 9 | e24102