Pharmacodynamic Models of Differential Bortezomib Signaling Across Several Cell Lines of Multiple Myeloma

Ramakrishnan, Vidya; Mager, Donald E.

doi:10.1002/psp4.12358

Cited by 6 publications

(4 citation statements)

References 51 publications

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“…Although the k deg,GILZm was same in both sexes, it was interesting to find a pronounced intertissue variability in this parameter across liver and uterus, consistent with previous findings (Ayyar et al, 2017). Similar observations of a "systems variability" in the degradation rate constants for some signaling proteins across several lines of multiple myeloma cells was recently reported (Ramakrishnan and Mager, 2019). The AUEC of hepatic GILZ enhancement was significantly greater in females compared with males ( Fig.…”

Section: Systems Modeling Of Corticosteroid-estrogen Antagonismsupporting

confidence: 90%

Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics, Part III: Estrous Cycle and Estrogen Receptor–Dependent Antagonism of Glucocorticoid-Induced Leucine Zipper (GILZ) Enhancement by Corticosteroids

Ayyar

DuBois

Almon

et al. 2019

J Pharmacol Exp Ther

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Our previous report examined the pharmacokinetics (PK) of methylprednisolone (MPL) and adrenal suppression after a 50 mg/kg IM bolus in male and female rats, and we described in detail the development of a minimal physiologically based pharmacokinetic/pharmacodynamic (mPBPK/ PD) model. In continuation of such assessments, we investigated sex differences in genomic MPL responses (PD). Message expression of the glucocorticoid-induced leucine zipper (GILZ) was chosen as a multitissue biomarker of glucocorticoid receptor (GR)-mediated drug response. Potential time-dependent interplay between sex hormone and glucocorticoid signaling in vivo was assessed by comparing the enhancement of GILZ by MPL in the uterus [high estrogen receptor (ER) density] and in liver (lower ER density) from male and female rats dosed within the proestrus (high estradiol/progesterone) and estrus (low estradiol/progesterone) phases of the rodent estrous cycle. An expanded-systems PD model of MPL considering circadian rhythms, multireceptor (ER and GR) control, and estrous variations delineated the determinants controlling receptor/gene-mediated steroid responses. Hepatic GILZ response was ∼3-fold greater in females, regardless of estrous stage, compared with males, driven predominantly by increased MPL exposure in females and a negligible influence of estrogen interaction. In contrast, GILZ response in the uterus during proestrus in females was 60% of that observed in estrus-phased females, despite no PK or receptor differences, providing in vivo support to the hypothesis of estrogen-mediated antagonism of glucocorticoid signaling. The developed model offers a mechanistic platform to assess the determinants of sex and tissue specificity in corticosteroid actions and, in turn, reveals a unique PD drughormone interaction occurring in vivo. SIGNIFICANCE STATEMENT Mechanisms relating to sex-based pharmacodynamic variability in genomic responses to corticosteroids have been unclear. Using combined experimental and systems pharmacology modeling approaches, sex differences in both pharmacokinetic and pharmacodynamic mechanisms controlling the enhancement of a sensitive corticosteroid-regulated biomarker, the glucocorticoid-induced leucine zipper (GILZ), were clarified in vivo. The multiscale minimal physiologically based pharmacokinetics/pharmacodynamic model successfully captured the experimental observations and quantitatively discerned the roles of the rodent estrous cycle (hormonal variation) and tissue specificity in mediating the antagonistic coregulation of GILZ gene synthesis. These findings collectively support the hypothesis that estrogens antagonize pharmacodynamic signaling of genomic corticosteroid actions in vivo in a timeand estrogen receptor-dependent manner.

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Section: Systems Modeling Of Corticosteroid-estrogen Antagonismsupporting

confidence: 90%

Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics, Part III: Estrous Cycle and Estrogen Receptor–Dependent Antagonism of Glucocorticoid-Induced Leucine Zipper (GILZ) Enhancement by Corticosteroids

Ayyar

DuBois

Almon

et al. 2019

J Pharmacol Exp Ther

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“…Our data support this particular combination of PIN/BTZ as being synergistic in reducing the viability of MM RPMI 8226 cells, although the extent of synergism seems to differ in the other two cell lines. Interestingly, BTZ has been shown to have similar effects in RPMI 8226 and U266 cells [ 42 ], while our study showed differing cytotoxic effects from PIN/BTZ in these two cell lines. Rather, we observed NCI-H929 cells to have similar cytotoxic effects to RPMI 8226 cells from PIN/BTZ treatment.…”

Section: Discussionmentioning

confidence: 43%

Cytotoxic and Apoptotic Effects of Pinostilbene and Bortezomib Combination Treatment on Human Multiple Myeloma Cells

Staskiewicz,

Wong,

Tucker

et al. 2023

IJMS

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Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow characterized by bone lesions, hypercalcemia, anemia, and renal failure. Bortezomib (BTZ), a common treatment for MM, is a proteasome inhibitor that induces apoptosis in MM cells. However, high doses of BTZ can be very toxic, signifying a need for a synergistic drug combination to improve treatment efficacy. Resveratrol (RES), a phenolic compound found in grapes, has been shown to inhibit MM cell growth. We sought to identify a synergistic combination of BTZ with a RES derivative and analyze the effects on reducing viability and inducing apoptosis in human MM cells. BTZ as well as RES and its derivatives pinostilbene (PIN) and piceatannol (PIC) decreased MM cell viability in a dose- and time-dependent manner and increased expression of cleaved proapoptotic proteins poly(ADP-ribose) polymerase 1 (PARP1) and caspase-3 in a dose-dependent manner. The combination of 5 nM BTZ and 5 μM PIN was identified to have synergistic cytotoxic effects in MM RPMI 8226 cells. MM RPMI 8226 cells treated with this combination for 24 h showed increased cleaved PARP1 and caspase-3 expression and higher percentages of apoptotic cells versus cells treated with the individual compounds alone. The treatment also showed increased apoptosis induction in MM RPMI 8226 cells co-cultured with human bone marrow stromal HS-5 cells in a Transwell model used to mimic the bone marrow microenvironment. Expression of oxidative stress defense proteins (catalase, thioredoxin, and superoxide dismutase) in RPMI 8226 cells were reduced after 24 h treatment, and cytotoxic effects of the treatment were ameliorated by antioxidant N-acetylcysteine (NAC), suggesting the treatment impacts antioxidant levels in RPMI 8226 cells. Our results suggest that this combination of BTZ and PIN decreases MM cell viability synergistically by inducing apoptosis and oxidative stress in MM cells.

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“…The mathematical model was validated qualitatively as a first effort, but importantly, the laboratory results confirm that the levels of caspase activation predicted biomarkers for clinical application (for example, see [48][49][50][51]). Here, two related rate constants that direct protein synthesis and degradation were found to contribute to the most variability in model output, caspase activation.…”

Section: Discussionmentioning

confidence: 79%

“…Sensitivity analyses have been commonly used following construction of computational ODE models to discover potential drug targets, therapy resistance, and other biomarkers for clinical application (for example, see [48][49][50][51]). Here, two related rate constants that direct protein synthesis and degradation were found to contribute to the most variability in model output, caspase activation.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic model of PARP1 inhibition and global sensitivity analyses can lead to cancer biomarker discovery

Mertins¹,

Isenberg²,

Reyes³

et al. 2023

Preprint

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Pharmacodynamic models provide inroads to understanding key mechanisms of action and may significantly improve patient outcomes in cancer with improved ability to determine therapeutic benefit. Additionally, these models may also lead to insights into potential biomarkers that can be utilized for prediction in prognosis and therapeutic decisions. As an example of this potential, here we present an advanced computational Ordinary Differential Equation (ODE) model of PARP1 signalling and downstream effects due to its inhibition. The model has been validated experimentally and further evaluated through a global sensitivity analysis. The sensitivity analysis uncovered two model parameters related to protein synthesis and degradation rates that were also found to contribute the most variability to the therapeutic prediction. Because this variability may define cancer patient subpopulations, we interrogated genomic, transcriptomic, and clinical databases, to uncover a biomarker that may correspond to patient outcomes in the model. In particular, GSPT2, a GTPase with translation function, was discovered and if mutations serve to alter catalytic activity, its presence may explain the variability in the model′s parameters. This work offers an analysis of ODE models, inclusive of model development, sensitivity analysis, and ensuing experimental data analysis, and demonstrates the utility of this methodology in uncovering biomarkers in cancer.

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Pharmacodynamic Models of Differential Bortezomib Signaling Across Several Cell Lines of Multiple Myeloma

Cited by 6 publications

References 51 publications

Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics, Part III: Estrous Cycle and Estrogen Receptor–Dependent Antagonism of Glucocorticoid-Induced Leucine Zipper (GILZ) Enhancement by Corticosteroids

Modeling Corticosteroid Pharmacokinetics and Pharmacodynamics, Part III: Estrous Cycle and Estrogen Receptor–Dependent Antagonism of Glucocorticoid-Induced Leucine Zipper (GILZ) Enhancement by Corticosteroids

Cytotoxic and Apoptotic Effects of Pinostilbene and Bortezomib Combination Treatment on Human Multiple Myeloma Cells

Pharmacodynamic model of PARP1 inhibition and global sensitivity analyses can lead to cancer biomarker discovery

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