Procaspase 3 activation by combination therapy

Patent metadata

Field	Value
Publication number	US-2016346277-A1
Application number	US-201615220361-A
Country	US
Kind code	A1
Filing date	Jul 26, 2016
Priority date	Mar 6, 2012
Publication date	Dec 1, 2016
Grant date	—

Abstract

The invention provides compositions and methods for the induction of cell death, for example, cancer cell death. Combinations of compounds and related methods of use are disclosed, including the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells. The disclosed drug combinations can have lower neurotoxicity effects than other compounds and combinations of compounds.

First claim

What is claimed is:

1 . A composition comprising:
(a) the compound PAC-1:

(b) a second active agent, wherein the second active agent is bortezomib, staurosporine, doxorubicin, cisplatin, carboplatin, paclitaxel, vincristine, oxaliplatin, mitomycin, irinotecan, etoposide, carmustine, methotrexate, 6-mercaptopurine, 5-fluorouracil, gemcitabine, or chlorambucil; and
(c) a pharmaceutically acceptable diluent, excipient, or carrier.

2 . The composition of claim 1 wherein the carrier comprises water and optionally a buffer, a cyclodextrin, or a combination thereof.

3 . The composition of claim 2 wherein the cyclodextrin is 2-hydroxypropyl-β-cyclodextrin.

4 . The composition of claim 1 wherein the concentration of PAC-1 is about 2 μM to about 50 μM.

5 . The composition of claim 4 wherein the concentration of PAC-1 is about 15 μM to about 30 μM.

6 . The composition of claim 1 wherein the concentration of the second active agent is about 25 nM to about 1 mM.

7 . The composition of claim 4 wherein the concentration of the second active agent is about 25 nM to about 1 mM.

8 . The composition of claim 4 wherein:
the second active agent is bortezomib and the concentration of bortezomib is about 50 nM to about 20 μM, or
the second active agent is staurosporine and the concentration of staurosporine is about 25 nM to about 200 nM, or
the second active agent is doxorubicin and the concentration of doxorubicin is about 50 nM to about 5 μM, or
the second active agent is cisplatin and the concentration of cisplatin is about 5 μM to about 150 μM, or
the second active agent is carboplatin and the concentration of carboplatin is about 5 μM to about 150 μM or
the second active agent is paclitaxel and the concentration of paclitaxel is about 0.5 nM to about 5 nM.

9 . The composition of claim 4 wherein:
the second active agent is bortezomib and the concentration of bortezomib is about 100 nM to about 5 μM, or
the second active agent is staurosporine and the concentration of staurosporine is about 50 nM to about 100 nM, or
the second active agent is doxorubicin and the concentration of doxorubicin is about 100 nM to about 1000 nM, or
the second active agent is cisplatin and the concentration of cisplatin is about 30 μM to about 100 μM, or
the second active agent is carboplatin and the concentration of carboplatin is about 25 μM to about 100 μM, or
the second active agent is paclitaxel and the concentration of paclitaxel is about 1 nM to about 3 nM.

10 . The composition of claim 5 wherein:
the second active agent is bortezomib and the concentration of bortezomib is about 100 nM to about 5 μM, or
the second active agent is staurosporine and the concentration of staurosporine is about 50 nM to about 100 nM, or
the second active agent is doxorubicin and the concentration of doxorubicin is about 100 nM to about 1000 nM, or
the second active agent is cisplatin and the concentration of cisplatin is about 30 μM to about 100 μM, or
the second active agent is carboplatin and the concentration of carboplatin is about 25 μM to about 100 μM, or
the second active agent is paclitaxel and the concentration of paclitaxel is about 1 nM to about 3 nM.

11 . The composition of claim 10 wherein:
the concentration of PAC-1 is about 15 μM to about 30 μM; and
the concentration of carboplatin is about 50 μM to about 100 μM.

12 . A method of inhibiting the growth or proliferation of cancer cells comprising contacting cancer cells with an effective amount of a composition of claim 1 , thereby inhibiting the growth or proliferation of the cancer cells.

13 . The method of claim 12 wherein the cancer cells are lymphoma cells, osteosarcoma cells, breast cancer cells, or ovarian carcinoma cells.

14 . A method of inducing apoptosis in a cancer cell comprising contacting the cancer cell with an effective amount of the compound PAC-1:

and an effective amount of a second active agent, wherein the second active agent is bortezomib, staurosporine, doxorubicin, cisplatin, carboplatin, or paclitaxel; wherein apoptosis is thereby induced in the cancer cell.

15 . The method of claim 14 wherein the contacting is in vitro or in vivo.

16 . The method of claim 14 wherein the cancer cell is contacted with PAC-1 and the second active agent concurrently, or
the cancer cell is contacted with PAC-1 prior to contacting the cancer cell with the second active agent, or
the cancer cell is contacted with PAC-1 after contacting the cancer cell with the second active agent.

17 . A method of treating a cancer in a patient in need thereof comprising administering to a patient, concurrently or sequentially, a therapeutically effective amount of the compound PAC-1:

and an effective amount of a second active agent, wherein the second active agent is bortezomib, staurosporine, doxorubicin, cisplatin, carboplatin, or paclitaxel; wherein the cancer is thereby treated.

18 . The method of claim 17 wherein the compound PAC-1 and the second active agent are administered sequentially.

19 . The method of claim 18 wherein the compound PAC-1 is administered before the second active agent.

20 . The method of claim 17 wherein the cancer is lymphoma, osteosarcoma, breast cancer, or ovarian cancer.

Assignees

• Univ Illinois
• Vanquish Oncology Inc

Inventors

• Hergenrother Paul J
• Botham Rachel C
• Fan Timothy M
• Gilbert Mark J
• Handley Michael K
• Roth Howard S
• Tarasow Theodore M

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K9/008

  comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI] · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title