Integrative systems control approach for reactivating Kaposi’s sarcoma-associated herpesvirus (KSHV) with combinatory drugs

UCLA, Los Angeles, CA 90095-1597, USA.
Integrative Biology (Impact Factor: 3.76). 01/2009; 1(1):123-30. DOI: 10.1039/b815225j
Source: PubMed


Cells serve as basic units of life and represent intricate biological molecular systems. The vast number of cellular molecules with their signaling and regulatory circuitries forms an intertwined network. In this network, each pathway interacts non-linearly with others through different intermediates. Thus, the challenge of manipulating cellular functions for desired outcomes, such as cancer eradication and controlling viral infection lies within the integrative system of regulatory circuitries. By using a closed-loop system control scheme, we can efficiently analyze biological signaling networks and manipulate their behavior through multiple stimulations on a collection of pathways. Specifically, we aimed to maximize the reactivation of Kaposi's Sarcoma-associated Herpesvirus (KSHV) in a Primary Effusion Lymphoma cell line. The advantage of this approach is that it is well-suited to study complex integrated systems; it circumvents the need for detailed information of individual signaling components; and it investigates the network as a whole by utilizing key systemic outputs as indicators.

Download full-text


Available from: Jeff Shamma, Aug 31, 2014
19 Reads
  • Source
    • "This study demonstrated the use of a double-objective FSC technique for the rapid identification of supplement combinations exhibiting the versatile osteogenic differentiation of MSC. The FSC strategy has previously been used for eradicating viral infections28, controlling herpes virus reactivation29, and maintaining human ES cells30. This method facilitates the identification of optimal drug combinations without any predisposing hypotheses. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Stem cell-based disease modeling presents unique opportunities for mechanistic elucidation and therapeutic targeting. The stable induction of fate-specific differentiation is an essential prerequisite for stem cell-based strategy. Bone morphogenetic protein 2 (BMP-2) initiates receptor-regulated Smad phosphorylation, leading to the osteogenic differentiation of mesenchymal stromal/stem cells (MSC) in vitro; however, it requires supra-physiological concentrations, presenting a bottleneck problem for large-scale drug screening. Here, we report the use of a double-objective feedback system control (FSC) with a differential evolution (DE) algorithm to identify osteogenic cocktails of extrinsic factors. Cocktails containing significantly reduced doses of BMP-2 in combination with physiologically relevant doses of dexamethasone, ascorbic acid, beta-glycerophosphate, heparin, retinoic acid and vitamin D achieved accelerated in vitro mineralization of mouse and human MSC. These results provide insight into constructive approaches of FSC to determine the applicable functional and physiological environment for MSC in disease modeling, drug screening and tissue engineering.
    Scientific Reports 12/2013; 3:3420. DOI:10.1038/srep03420 · 5.58 Impact Factor
  • Source
    • "The search algorithm plays an important role in the FSC scheme, which determines the efficiency and accuracy of the exploration. We used the differential evolution algorithm to perform a parallel exploration in the chemical optimization, due to its easy operation and previous successful application [16, 21, 22]. The principle and detailed application of the differential evolution algorithm in our FSC scheme were introduced in the supporting information (Figure 1(S), Supporting information, see supplementary materials available online at "
    [Show abstract] [Hide abstract]
    ABSTRACT: Identifying potent drug combination from a herbal mixture is usually quite challenging, due to a large number of possible trials. Using an engineering approach of the feedback system control (FSC) scheme, we identified the potential best combinations of four flavonoids, including formononetin, ononin, calycosin, and calycosin-7-O- β -D-glucoside deriving from Astragali Radix (AR; Huangqi), which provided the best biological action at minimal doses. Out of more than one thousand possible combinations, only tens of trials were required to optimize the flavonoid combinations that stimulated a maximal transcriptional activity of hypoxia response element (HRE), a critical regulator for erythropoietin (EPO) transcription, in cultured human embryonic kidney fibroblast (HEK293T). By using FSC scheme, 90% of the work and time can be saved, and the optimized flavonoid combinations increased the HRE mediated transcriptional activity by ~3-fold as compared with individual flavonoid, while the amount of flavonoids was reduced by ~10-fold. Our study suggests that the optimized combination of flavonoids may have strong effect in activating the regulatory element of erythropoietin at very low dosage, which may be used as new source of natural hematopoietic agent. The present work also indicates that the FSC scheme is able to serve as an efficient and model-free approach to optimize the drug combination of different ingredients within a herbal decoction.
    Evidence-based Complementary and Alternative Medicine 04/2013; 2013(6):541436. DOI:10.1155/2013/541436 · 1.88 Impact Factor
  • Source
    • "A Medicinal Algorithmic Combinatorial Screen based on the hill climbing algorithm was demonstrated for screening anti-cancer drug cocktails [27]. A parallel search scheme, Differential Evolution algorithm, was demonstrated for identifying antiviral cocktails for Kaposi's Sarcoma-associated Herpesvirus [28]. These search algorithms, which test drug cocktails sequentially, are especially effective for biological systems with smooth response surfaces in the parametric space. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Many bacterial pathogens are becoming drug resistant faster than we can develop new antimicrobials. To address this threat in public health, a metamodel antimicrobial cocktail optimization (MACO) scheme is demonstrated for rapid screening of potent antibiotic cocktails using uropathogenic clinical isolates as model systems. With the MACO scheme, only 18 parallel trials were required to determine a potent antimicrobial cocktail out of hundreds of possible combinations. In particular, trimethoprim and gentamicin were identified to work synergistically for inhibiting the bacterial growth. Sensitivity analysis indicated gentamicin functions as a synergist for trimethoprim, and reduces its minimum inhibitory concentration for 40-fold. Validation study also confirmed that the trimethoprim-gentamicin synergistic cocktail effectively inhibited the growths of multiple strains of uropathogenic clinical isolates. With its effectiveness and simplicity, the MACO scheme possesses the potential to serve as a generic platform for identifying synergistic antimicrobial cocktails toward management of bacterial infection in the future.
    PLoS ONE 11/2010; 5(11):e15472. DOI:10.1371/journal.pone.0015472 · 3.23 Impact Factor
Show more