Pharmacodynamic Modeling of Anti-Cancer Activity of Tetraiodothyroacetic Acid in a Perfused Cell Culture System

Unmodified or as a poly[lactide-co-glycolide] nanoparticle, tetraiodothyroacetic acid (tetrac) acts at the integrin αvβ3 receptor on human cancer cells to inhibit tumor cell proliferation and xenograft growth. To study in vitro the pharmacodynamics of tetrac formulations in the absence of and in conjunction with other chemotherapeutic agents, we developed a perfusion bellows cell culture system. Cells were grown on polymer flakes and exposed to various concentrations of tetrac, nano-tetrac, resveratrol, cetuximab, or a combination for up to 18 days. Cells were harvested and counted every one or two days. Both NONMEM VI and the exact Monte Carlo parametric expectation maximization algorithm in S-ADAPT were utilized for mathematical modeling. Unmodified tetrac inhibited the proliferation of cancer cells and did so with differing potency in different cell lines. The developed mechanism-based model included two effects of tetrac on different parts of the cell cycle which could be distinguished. For human breast cancer cells, modeling suggested a higher sensitivity (lower IC50) to the effect on success rate of replication than the effect on rate of growth, whereas the capacity (Imax) was larger for the effect on growth rate. Nanoparticulate tetrac (nano-tetrac), which does not enter into cells, had a higher potency and a larger anti-proliferative effect than unmodified tetrac. Fluorescence-activated cell sorting analysis of harvested cells revealed tetrac and nano-tetrac induced concentration-dependent apoptosis that was correlated with expression of pro-apoptotic proteins, such as p53, p21, PIG3 and BAD for nano-tetrac, while unmodified tetrac showed a different profile. Approximately additive anti-proliferative effects were found for the combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab. Our in vitro perfusion cancer cell system together with mathematical modeling successfully described the anti-proliferative effects over time of tetrac and nano-tetrac and may be useful for dose-finding and studying the pharmacodynamics of other chemotherapeutic agents or their combinations

Thyroid Hormone Replacement Therapy in Patients with Various Types of Cancer

Primary hypothyroidism is a common endocrine disorder that is effectively treated with l-thyroxine (T4) replacement. Preclinical and limited clinical evidence, however, indicates that T4 is a growth factor for a variety of cancers, acting at the thyroid hormone receptor on plasma membrane integrin αvβ3. T4 is the primary ligand for this receptor, whereas 3,5,3′-triiodo-l-thyronine (T3) is the principal intracellular thyroid hormone analogue. The evidence is reviewed here that T4 is a proliferative for breast, lung, kidney and prostate cancers and for glioblastoma, regulates cancer cell respiration and is a pro-angiogenic factor in established tumors. The recommendation is made that T3 be considered alternative replacement treatment for patients with primary hypothyroidism who also have cancer

Tetrac and NDAT Induce Anti-proliferation via Integrin αvβ3 in Colorectal Cancers With Different K-RAS Status

Colorectal cancer is a serious medical problem in Taiwan. New, effective therapeutic approaches are needed. The selection of promising anticancer drugs and the transition from pre-clinical investigations to clinical trials are often challenging. The deaminated thyroid hormone analog (tetraiodothyroacetic acid, tetrac) and its nanoparticulate analog (NDAT) have been shown to have anti-proliferative activity in vitro and in xenograft model of different neoplasms, including colorectal cancers. However, mechanisms involved in tetrac- and NDAT-induced anti-proliferation in colorectal cancers are incompletely understood. We have investigated possible mechanisms of tetrac and NDAT action in colorectal cancer cells, using a perfusion bellows cell culture system that allows efficient, large-scale screening for mechanisms of drug actions on tumor cells. Although integrin αvβ3 in K-RAS wild type colorectal cancer HT-29 cells was far less than that in K-RAS mutant HCT116 cells, HT-29 was more sensitive to both tetrac and NDAT. Results also indicate that both tetrac and NDAT bind to tumor cell surface integrin αvβ3, and the agents may have different mechanisms of anti-proliferation in colorectal cancer cells. K-RAS status appears to play an important role in drug resistance that may be encountered in treatment with this drug combination

Targeted delivery of cisplatin to tumor xenografts via the nanoparticle component of nano-diamino-tetrac

Aim: Nano-diamino-tetrac (NDAT) targets a receptor on integrin alpha v beta 3; alpha v beta 3 is generously expressed by cancer cells and dividing endothelial cells and to a small extent by nonmalignant cells. The tetrac (tetraiodothyroacetic acid) of NDAT is covalently bound to a poly(lactic-co-glycolic acid) nanoparticle that encapsulates anticancer drugs. We report NDAT delivery efficiency of cisplatin to agent-susceptible urinary bladder cancer xenografts. Materials & methods: Cisplatin-loaded NDAT (NDAT-cisplatin) was administered to xenograft-bearing nude mice. Tumor size response and drug content were measured. Results: Intratumoral drug concentration was up to fivefold higher (p NDAT without cisplatin > cisplatin alone. Conclusion: NDAT markedly enhances cisplatin delivery to urinary bladder cancer xenografts and increases drug efficacy.NanoPharmaceuticals LLC (NY, USA)NanoPharmaceuticals LL

Non-genomic Actions of Thyroid Hormones Regulate the Growth and Angiogenesis of T Cell Lymphomas

T-cell lymphomas (TCL) are a heterogeneous group of aggressive clinical lymphoproliferative disorders with considerable clinical, morphological, immunophenotypic, and genetic variation, including ~10–15% of all lymphoid neoplasms. Several evidences indicate an important role of the non-neoplastic microenvironment in promoting both tumor growth and dissemination in T cell malignancies. Thus, dysregulation of integrin expression and activity is associated with TCL survival and proliferation. We found that thyroid hormones acting via the integrin αvβ3 receptor are crucial factors in tumor microenvironment (TME) affecting the pathophysiology of TCL cells. Specifically, TH-activated αvβ3 integrin signaling promoted TCL proliferation and induced and an angiogenic program via the up-regulation of the vascular endothelial growth factor (VEGF). This was observed both on different TCL cell lines representing the different subtypes of human hematological malignancy, and in preclinical models of TCL tumors xenotransplanted in immunodeficient mice as well. Moreover, development of solid tumors by inoculation of murine TCLs in syngeneic hyperthyroid mice, showed increased tumor growth along with increased expression of cell cycle regulators. The genomic or pharmacological inhibition of integrin αvβ3 decreased VEGF production, induced TCL cell death and decreased in vivo tumor growth and angiogenesis. Here, we review the non-genomic actions of THs on TCL regulation and their contribution to TCL development and evolution. These actions not only provide novel new insights on the endocrine modulation of TCL, but also provide a potential molecular target for its treatment

Effetto non genomico e genomico degli ormoni tiroidei T3 e T4 sull'angiogenesi in cellule endoteliali umane cardiache

Gli ormoni tiroidei (TH) svolgono ruoli fondamentali nella crescita, sviluppo e metabolismo nella maggior parte dei tipi cellulari nei vertebrati. Fino a pochi anni fa i ricercatori pensavano che il principale meccanismo di TH sull’angiogenesi avvenisse tramite l’interazione di TH con i recettori tiroidei nucleari. Recentemente, diversi studi sembrano invece indicare che l’effetto degli ormoni tiroidei, T3 (3,5,3’-triiodo-L-tironina) e T4 (L-tiroxina) sull’angiogenesi avviene principalmente attraverso un’azione non genomica che inizia a livello di un recettore di membrana integrina αVβ3, trasducendo segnali pro-angiogenici che derivano dall’attivazione a cascata di MAPK (ERK-1/2) con conseguenti effetti genomici. Il recettore integrina αVβ3 è ampiamente espresso sulla membrana plasmatica di cellule endoteliali, cellule muscolari lisce, monociti e piastrine; la sua porzione extracellulare possiede un sito di legame che riconosce la sequenza Arg-Gly-Asp (RGD) presente sui ligandi T3 e T4. Inoltre è stato visto che l’acido tetraiodotiroacetico (Tetrac), un analogo della T4, ha un effetto anti-angiogenico poiché antagonista di T3 e T4 sul recettore plasmatico dell’integrina. Lo scopo di questo lavoro è quello di valutare l’effetto di T3 e T4 sull’angiogenesi in cellule endoteliali cardiache (HMVEC-C), considerando in primo luogo l’effetto non genomico e, in secondo luogo, l’effetto genomico. L’angiogenesi è stata valutata in vitro tramite saggi di proliferazione, migrazione e formazione di tubuli su Matrigel come substrato, in presenza e assenza di Tetrac. Utilizzando la tecnica del western blot, sono state analizzate le chinasi delle vie di segnale, caratterizzate dall’attivazione di MAPK, ERK1/2 mediate dal legame di T3,T4 e Tetrac con il recettore dell’integrina. Mediante RT-PCR è stata valutata l’espressione dell’integrina di membrana αVβ3 e di geni legati all’angiogenesi come VEGF, vascular endothelial growth factor, AAMP, angio-associated migratory protein, angiopoietina 1 e 2. I nostri risultati indicano che T3 e T4 stimolano direttamente l’angiogenesi mediata dall’integrina in cellule endoteliali umane cardiache in tutti gli aspetti considerati: aumento significativo della densità capillare, proliferazione e migrazione cellulare. In presenza di Tetrac, antagonista degli ormoni tiroidei sul recettore, si è osservata una riduzione di questi effetti. I nostri esperimenti suggeriscono anche il ruolo di T3 e T4 nell’attivazione di vie di segnale intracellulari come MAPK-ERK1/2 e il coinvolgimento di geni legati all’angiogenesi come AAMP. Nell’insieme i nostri dati indicano un potenziale effetto angiogenico degli ormoni tiroidei, mediato da integrina αVβ3, suggerendo che T3 e T4 possono essere considerati come trattamento farmacologico per malattie cardiache in cui è stata riportata una riduzione della densità capillare. Infine è stata confermata l’azione inibitoria del Tetrac sull’angiogenesi, suggerendo il suo ruolo chiave come farmaco anti-tumoral

Cancer Nanomedicine

This special issue brings together cutting edge research and insightful commentary on the currentl state of the Cancer Nanomedicine field

The HBP1 tumor suppressor is a negative epigenetic regulator of MYCN driven neuroblastoma through interaction with the PRC2 complex

C