Compositions including triciribine and bortezomib and derivatives thereof and methods of use thereof

Inactive Publication Date: 2010-01-14
UNIV OF SOUTH FLORIDA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]The present invention provides novel therapeutic regimens of triciribine, triciribine phosphate and related compounds in combination with bortezomib and derivatives thereof and derivatives thereof to treat tumors or cancer in a subject while limiting systemic toxicity. The invention is based on the discovery that tumors or cancers, which overexpress Akt kinase are particularly sensitive to the cytotoxic effects of TCN and related compounds and a synergistic affect would arise with a combination of bortezomib salts or derivatives thereof and derivatives thereof. The

Problems solved by technology

Cancer cells are often shaped differently from healthy cells, do not function properly, and can spread into many areas of the body.
However, in other cases, the myeloma cells collect in many bones, forming many bone tumors.
These factors can cause numerous cellular effects, for example, they can result in overexpression of a gene product.
This in turn results in fundamental defects in cell physiology which dictate malignancy.
Current treatments of cancer and related diseases have limited effectiveness a

Method used

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  • Compositions including triciribine and bortezomib and derivatives thereof and methods of use thereof
  • Compositions including triciribine and bortezomib and derivatives thereof and methods of use thereof
  • Compositions including triciribine and bortezomib and derivatives thereof and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

8.1. Example 1

In Vitro Screening

[0229]Cell Lines and NCI Diversity Set. All cell lines can be purchased from ATCC or described previously (Cheng et al., 1997, Oncogene 14: 2793-2801; West et al., 2002, Drug Resist Updat 5: 234-248; Satyamoorthy et al., 2001, Cancer Res 61: 7318-7324). The NCI Structural Diversity Set is a library of 1,992 compounds selected from the approximately 140,000-compound NCI drug depository. In-depth data on the selection, structures, and activities of these diversity set compounds can be found on the NCI Developmental Therapeutics Program web site.

[0230]Screening for Inhibition of Akt-transformed Cell Growth. AKT2 transformed NIH3T3 cells or LXSN vector-transfected NIH3T3 control cells (Cheng et al., 1997, Oncogene 14: 2793-2801) are plated into 96-well tissue culture plate. Following treatment with 5 μM of NCI Diversity Set compound, cell growth can be detected with CellTier 96 One Solution Cell Proliferation kit (Promega). Compounds that inhibit growth i...

example 2

8.2 Example 2

Antitumor Activity in the Nude Mouse Tumor Xenograft Model

[0237]Tumor cells can be harvested, suspended in PBS, and can be injected s.c. into the right and left flanks (2×106 cells / flank) of 8-week-old female nude mice as reported previously (Sun et al., 1999, Cancer Res 59: 4919-4926). When tumors reach about 100-150 mm3, animals are randomized and dosed i.p. with 0.2 ml vehicle of the triciribine compound and / or one or more platinum compounds daily. Control animals receive DMSO (20%) vehicle, whereas treated animals can be injected with API-2 (1 mg / kg / day) in 20% DMSO.

[0238]API-2 Inhibits the Growth of Tumors in Nude Mice that Overexpress Akt. Frequent overexpression / activation and / or amplification of AKT1 and AKT2 in human ovarian and pancreatic cancer was shown (Cheng et al., AKT signal transduction pathway in oncogenesis, in Schwab D (ed.) Encyclopedic Reference of Cancer, Springer, pp 35-7). Inhibition of Akt pathway by inhibitors of PI3K, HSP70, Src and farnesylt...

example 3

8.3 Example 3

TCN Directly Inhibits Wild Type Akt Kinase Activity

[0239]API-2 (TCN) can directly inhibit wild type Akt kinase activity induced by PDK1 in vitro (FIG. 1). This result supports that API-2 is a direct Akt inhibitor and that the underlying mechanism may be API-2 binding to PH domain and / or threonine-308 of Akt. An In vitro kinase assay is performed with recombinant of PDK1 and Akt in a kinase buffer containing phosphatidylinositol-3,4,5-P3 (PIP3). API-2 and histone H2B as substrate. After incubation of 30 min, the reactions were separated by SDS-PAGE and exposed in a film.

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Abstract

This application relates to combination therapies including triciribine and related compounds and bortezomib and derivatives thereof analogs and compositions with reduced toxicity for the treatment and prevention of tumors, cancer, and other disorders associated with abnormal cell proliferation.

Description

[0001]This application is a continuation-in-part of U.S. application Ser. No. 11 / 096,082, filed Mar. 25, 2005, which claims the benefit of U.S. provisional patent application No. 60 / 557,599 filed Mar. 29, 2004, which is incorporated herein by reference.1. FIELD OF THE INVENTION[0002]This application relates to combination therapies including triciribine compounds and bortezomib and derivatives thereof and compositions with reduced toxicity for the treatment and prevention of tumors, cancer, and other disorders associated with abnormal cell proliferation.2. BACKGROUND OF THE INVENTION[0003]Cancer is an abnormal growth of cells. Cancer cells rapidly reproduce despite restriction of space, nutrients shared by other cells, or signals sent from the body to stop reproduction. Cancer cells are often shaped differently from healthy cells, do not function properly, and can spread into many areas of the body. Abnormal growths of tissue, called tumors, are clusters of cells that are capable of...

Claims

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Application Information

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IPC IPC(8): A61K31/70A61P35/00
CPCA61K31/7076A61K31/7064A61K31/69A61K38/05A61P35/00
Inventor CHENG, JIN Q.SEBTI, SAID M.
Owner UNIV OF SOUTH FLORIDA
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