Pancreatic cancer treatment using Na+/K+ ATPase inhibitors
The reagent, pharmaceutical formulation, kit, and methods of the invention provides a new approach for treating pancreatic cancers. The invention provides the use of Na + /K + -ATPase inhibitors, such as cardiac glycosides (e.g. ouabain and proscillaridin, etc.), either alone or in combination with other standard therapeutic agents (chemo- or radio-therapies, etc.) for treating pancreatic cancers.
1 . A pharmaceutical formulation comprising a Na + /K + -ATPase inhibitor, either alone or in combination with an anti-cancer agent, formulated in a pharmaceutically acceptable excipient and suitable for use in humans to treat pancreatic cancer.
2 . A kit for treating a patient having pancreatic cancer, comprising a Na + /K + -ATPase inhibitor, either alone or in combination with an anti-cancer agent, each formulated in premeasured doses for administration to the patient.
3 . A method for treating a patient having pancreatic cancer, comprising administering to the patient an effective amount of a Na + /K + -ATPase inhibitor, either alone or in combination with an anti-cancer agent.
4 . A method for promoting treatment of a patient having pancreatic cancer, comprising packaging, labeling and/or marketing a Na + /K + -ATPase inhibitor, either alone or in combination with an anti-cancer agent, for use in therapy for treating the patient.
5 . A method for promoting treatment of a patient having pancreatic cancer, comprising packaging, labeling and/or marketing an anti-cancer agent to be used in conjoint therapy with a Na + /K + -ATPase inhibitor for treating the patient.
6 . The pharmaceutical formulation of claim 1 , wherein the Na + /K + -ATPase inhibitor is a cardiac glycoside.
7 . The pharmaceutical formulation of claim 6 , wherein the cardiac glycoside, when in combination with the anti-cancer agent, has an IC 50 for killing one or more different cancer cell lines that is at least 2 fold less than the IC 50 of the cardiac glycoside alone.
8 . The pharmaceutical formulation of claim 6 , wherein the cardiac glycoside, when in combination with the anti-cancer agent, has an EC 50 for treating the pancreatic cancer that is at least 2 fold less than the EC 50 of the cardiac glycoside alone.
9 . The pharmaceutical formulation of claim 6 , wherein the cardiac glycoside is represented by the general formula:
wherein
R represents a glycoside of 1 to 6 sugar residues;
R 1 represents hydrogen, —OH or ═O;
R 2 , R 3 , R 4 , R 5 , and R 6 each independently represents hydrogen or —OH; and
R 7 represents
which cardiac glycoside has an IC 50 for killing one or more different cancer cell lines of 500 nM or less.
10 . The pharmaceutical formulation of claim 6 , wherein the cardiac glycoside comprises a steroid core with either a pyrone substituent at C17 (the “bufadienolides form”), or a butyrolactone substituent at C17 (the “cardenolide” form).
11 . The pharmaceutical formulation of claim 6 , wherein the cardiac glycoside is ouabain or proscillaridin.
12 . The pharmaceutical formulation of claim 6 , wherein the anti-cancer agent induces redox-sensitive transcription.
13 . The pharmaceutical formulation of claim 12 , wherein the anti-cancer agent induces HIF-1α-dependent transcription.
14 . The pharmaceutical formulation of claim 6 , wherein the anti-cancer agent induces mitochondrial dysfunction and/or caspase activation.
15 . The pharmaceutical formulation of claim 6 , wherein the anti-cancer agent induces cell cycle arrest at G2/M in the absence of said Cardiac glycoside.
16 . The pharmaceutical formulation of claim 6 , wherein said anti-cancer agent is an inhibitor of chromatin function.
17 . The pharmaceutical formulation of claim 16 , wherein said anti-cancer agent is a DNA topoisomerase inhibitor.
18 . The pharmaceutical formulation of claim 16 , wherein said anti-cancer agent is a microtubule inhibiting drug.
19 . The pharmaceutical formulation of claim 6 , wherein said anti-cancer agent is a DNA damaging agent.
20 . The pharmaceutical formulation of claim 6 , wherein said anti-cancer agent is an antimetabolite.
21 . The pharmaceutical formulation of claim 6 , wherein said anti-cancer agent is a DNA synthesis inhibitor.
22 . The pharmaceutical formulation of claim 6 , wherein said anti-cancer agent is a DNA binding agent.