Anti-neoplastic compositions comprising extracts of black cohosh

Abstract

A method for treating, preventing or ameliorating breast cancer is provided by administering a synergistic amount of digitoxin and either actein or an extract of black cohosh comprising triterpene glycosides, and optionally another chemopreventive agent which may be paclitaxel. Methods for treating or preventing a neoplasia using a synergistic combination, and compositions of a synergistic combination of a cardiac glycoside and either actein or an extract of black cohosh comprising triterpene glycosides, and optionally another chemopreventive agent which may be a taxane are also provided. The compositions may also be used in a method for modulating Na + K + ATPase activity. In addition, a method for inhibiting the progression or development of breast cancer in vivo by administering either actein or an extract of black cohosh comprising triterpene glycosides and optionally at least one other chemoprotective agent is provided.

1 . A method for treating, preventing or ameliorating breast cancer comprising administering to a patient in need thereof a composition comprising a synergistic amount of digitoxin and an extract of black cohosh comprising a triterpene glycoside, and a pharmaceutically acceptable carrier, and optionally an effective amount of at least one additional chemopreventive or chemotherapeutic agent. 
     
     
         2 . A method for treating, preventing or ameliorating breast cancer comprising administering to a patient in need thereof a composition comprising a synergistic amount of digitoxin and actein, and a pharmaceutically acceptable carrier, and optionally an effective amount of at least one additional chemopreventive or chemotherapeutic agent. 
     
     
         3 . A method for treating or preventing neoplasia in a subject comprising administering to the subject an amount of an extract of black cohosh comprising a triterpene glycoside, which amount of the black cohosh is effective to treat or prevent neoplasia, in combination with an amount of an a cardiac glycoside which is effective to treat or prevent the neoplasia, and optionally an effective amount of at least one additional chemopreventive or chemotherapeutic agent. 
     
     
         4 . The method of  claim 3 , wherein the extract comprises actein, and optionally further comprises cimigenol. 
     
     
         5 . The method of  claim 3 , wherein the extract is selected from the group consisting of an ethyl acetate extract of black cohosh and an n-butanolic fraction of an EtOH/water extract of black cohosh. 
     
     
         6 . A method for treating or preventing neoplasia in a subject comprising administering to the subject an amount of actein effective to treat or prevent neoplasia, in combination with an amount of a cardiac glycoside which is effective to treat or prevent the neoplasia, and optionally an effective amount of at least one additional chemopreventive or chemotherapeutic agent. 
     
     
         7 . The method according to  claim 3  wherein the neoplasia is a carcinoma. 
     
     
         8 . The method according to  claims 6  wherein the neoplasia is a carcinoma. 
     
     
         9 . The method of  claim 7  wherein the carcinoma is breast cancer. 
     
     
         10 . The method of  claim 8  wherein the carcinoma is breast cancer. 
     
     
         11 . The method according to  claim 3 , wherein the cardiac glycoside is selected from the group consisting of digitoxin, ouabain, proscillaridin A, digoxin, lanatoside C, and combinations thereof. 
     
     
         12 . The method according to  claim 6 , wherein the cardiac glycoside is selected from the group consisting of digitoxin, ouabain, proscillaridin A, digoxin, lanatoside C, and combinations thereof. 
     
     
         13 . The method of  claim 11 , wherein the cardiac glycoside is digitoxin. 
     
     
         14 . The method of  claim 12 , wherein the cardiac glycoside is digitoxin. 
     
     
         15 . The method according to  claim 13  wherein the actein and digitoxin are in amounts that result in a synergistic anti-neoplastic effect. 
     
     
         16 . The method according to  claim 14  wherein the actein and digitoxin are in amounts that result in a synergistic anti-neoplastic effect. 
     
     
         17 . The method according to  claim 4  wherein the amount of actein that is effective to treat or prevent the neoplasia is from about 0.2 μg/ml to about 40.0 μg/ml. 
     
     
         18 . The method according to  claim 6  wherein the amount of actein that is effective to treat or prevent the neoplasia is from about 0.2 μg/ml to about 40.0 μg/ml. 
     
     
         19 . The method according to  claim 15 , wherein the amount of actein is from about 0.2 μg/ml to about 2 μg/ml and the digitoxin is in an amount of from about 0.01 μg/ml to about 0.8 μg/ml, or the amount of actein is from about 2 μg/ml to about 20 μg/ml and the digitoxin is in an amount of from about 0.0004 μg/ml to about 5 μg/ml. 
     
     
         20 . The method according to  claim 16 , wherein the amount of actein is from about 0.2 μg/ml to about 2 μg/ml and the digitoxin is in an amount of from about 0.01 μg/ml to about 0.8 μg/ml, or the amount of actein is from about 2 μg/ml to about 20 μg/ml and the digitoxin is in an amount of from about 0.0004 μg/ml to about 5 μg/ml. 
     
     
         21 . A method for modulating Na + -K + -ATPase activity comprising contacting a cell that expresses Na + -K + -ATPase with an extract of black cohosh comprising a triterpene glycoside and a cardiac glycoside, and optionally at least one additional chemopreventive or chemotherapeutic agent. 
     
     
         22 . A method for modulating Na + -K + -ATPase activity comprising contacting a cell that expresses Na + -K + -ATPase with actein and a cardiac glycoside, and optionally at least one additional chemopreventive or chemotherapeutic agent. 
     
     
         23 . The method according to  claim 21  wherein the cardiac glycoside is digitoxin. 
     
     
         24 . The method according to  claim 22  wherein the cardiac glycoside is digitoxin. 
     
     
         25 . A method for modulating a growth inhibitory effect of digitoxin on a carcinoma, which comprises contacting the carcinoma with digitoxin and an effective amount of an extract of black cohosh comprising a triterpene glycoside, which results in a synergistic effect of the digitoxin on the carcinoma, and optionally an effective amount of at least one additional chemopreventive or chemotherapeutic agent. 
     
     
         26 . A method for modulating a growth inhibitory effect of digitoxin on a carcinoma which comprises contacting the carcinoma with digitoxin and an effective amount of actein, which results in a synergistic effect of the digitoxin on the carcinoma, and optionally an effective amount of at least one additional chemopreventive or chemotherapeutic agent. 
     
     
         27 . The method of  claim 25  wherein the carcinoma is breast cancer. 
     
     
         28 . The method of  claim 26  wherein the carcinoma is breast cancer. 
     
     
         29 . A composition for use in treating or preventing neoplasia comprising an effective anti-neoplastic amount of an extract of black cohosh comprising a triterpene glycoside and an effective anti-neoplastic amount of a cardiac glycoside, and optionally an effective amount of at least one additional chemopreventive or chemotherapeutic agent. 
     
     
         30 . The composition of  claim 29 , wherein the extract comprises actein, and optionally further comprises cimigenol. 
     
     
         31 . The composition of  claim 29 , wherein the extract is selected from the group consisting of an ethyl acetate extract of black cohosh and an n-butanolic fraction of an EtOH/water extract of black cohosh. 
     
     
         32 . A composition for use in treating or preventing neoplasia comprising an effective anti-neoplastic amount of actein and an effective anti-neoplastic amount of a cardiac glycoside, and optionally an effective amount of at least one additional chemopreventive or chemotherapeutic agent. 
     
     
         33 . The composition according to  claim 31 , wherein the cardiac glycoside is selected from the group consisting of digitoxin, ouabain, proscillaridin A, digoxin, lanatoside C, and combinations thereof. 
     
     
         34 . The composition according to  claim 32 , wherein the cardiac glycoside is selected from the group consisting of digitoxin, ouabain, proscillaridin A, digoxin, lanatoside C, and combinations thereof. 
     
     
         35 . The composition of  claim 33 , wherein the cardiac glycoside is digitoxin. 
     
     
         36 . The composition of  claim 34 , wherein the cardiac glycoside is digitoxin. 
     
     
         37 . The composition of  claim 35 , wherein actein and digitoxin are in amounts that result in a synergistic anti-neoplastic effect. 
     
     
         38 . The composition of  claim 36 , wherein actein and digitoxin are in amounts that result in a synergistic anti-neoplastic effect. 
     
     
         39 . The composition according to  claim 33 , wherein the effective anti-neoplastic amount of actein is from about 0.2 μg/ml to about 40.0 μg/ml. 
     
     
         40 . The composition according to  claim 34 , wherein the effective anti-neoplastic amount of actein is from about 0.2 μg/ml to about 40.0 μg/ml. 
     
     
         41 . The composition according to  claim 39 , wherein the cardiac glycoside is digitoxin and the amount of actein is from about 0.2 μg/ml to about 2 μg/ml and the amount of digitoxin is from about 0.01 μg/ml to about 0.8 μg/ml, or the amount of actein is from about 2 μg/ml to about 20 μg/ml, and the digitoxin is in an amount of from about 0.0004 μg/ml to about 5 μg/ml. 
     
     
         42 . The composition according to  claim 40 , wherein the cardiac glycoside is digitoxin and the amount of actein is from about 0.2 μg/ml to about 2 μg/ml and the amount of digitoxin is from about 0.01 μg/ml to about 0.8 μg/ml, or the amount of actein is from about 2 μg/ml to about 20 μg/ml, and the digitoxin is in an amount of from about 0.0004 μg/ml to about 5 μg/ml. 
     
     
         43 . A pharmaceutical composition which comprises a composition according to  claim 37 , and a pharmaceutically acceptable carrier. 
     
     
         44 . A pharmaceutical composition which comprises a composition according to  claim 38 , and a pharmaceutically acceptable carrier. 
     
     
         45 . The method according to  claim 1  wherein the at least one additional chemopreventive or chemotherapeutic agent is paclitaxel. 
     
     
         46 . The method according to  claim 2  wherein the at least one additional chemopreventive or chemotherapeutic agent is paclitaxel. 
     
     
         47 . The method according to  claim 3  wherein the at least one additional chemopreventive or chemotherapeutic agent is paclitaxel. 
     
     
         48 . The method according to  claim 6  wherein the at least one additional chemopreventive or chemotherapeutic agent is a taxane. 
     
     
         49 . The method according to  claim 21  wherein the at least one additional chemopreventive or chemotherapeutic agent is paclitaxel. 
     
     
         50 . The method according to  claim 22  wherein the at least one additional chemopreventive or chemotherapeutic agent is a taxane. 
     
     
         51 . The method of  claim 48  wherein the taxane is selected from the group consisting of paclitaxel, docetaxel, and mixtures thereof. 
     
     
         52 . The method of  claim 50  wherein the taxane is selected from the group consisting of paclitaxel, docetaxel, and mixtures thereof. 
     
     
         53 . The method of  claim 51  wherein the taxane is paclitaxel. 
     
     
         54 . The method of  claim 52  wherein the taxane is paclitaxel. 
     
     
         55 . The method according to  claim 45  wherein the paclitaxel is in an amount that results in a synergistic effect with the digitoxin and the triterpene glycoside. 
     
     
         56 . The method according to  claim 46  wherein the paclitaxel is in an amount that results in a synergistic effect with the digitoxin and the actein. 
     
     
         57 . The method according to  claim 47  wherein the paclitaxel is in an amount that results in a synergistic effect with the cardiac glycoside and the triterpene glycoside. 
     
     
         58 . The method according to  claim 53  wherein the paclitaxel is in an amount that results in a synergistic effect with the cardiac glycoside and the actein. 
     
     
         59 . The method according to  claim 49  wherein the paclitaxel is in an amount that results in a synergistic effect with the cardiac glycoside and the triterpene glycoside. 
     
     
         60 . The method according to  claim 54  wherein the paclitaxel is in an amount that results in a synergistic effect with the cardiac glycoside and the actein. 
     
     
         61 . The composition according to  claim 30  wherein the at least one additional chemopreventive or chemotherapeutic agent is paclitaxel. 
     
     
         62 . The composition according to  claim 32  wherein the at least one additional chemopreventive or chemotherapeutic agent is a taxane. 
     
     
         63 . The composition of  claim 62  wherein the taxane is selected from the group consisting of paclitaxel, docetaxel, and mixtures thereof. 
     
     
         64 . The composition of  claim 63  wherein the taxane is paclitaxel. 
     
     
         65 . The composition according to  claim 61  wherein the paclitaxel is in an amount that results in a synergistic effect with the cardiac glycoside and the actein. 
     
     
         66 . The composition according to  claim 64  wherein the paclitaxel is in an amount that results in a synergistic effect with the cardiac glycoside and the actein. 
     
     
         67 . A pharmaceutical composition which comprises the composition of  claim 66  and a pharmaceutically acceptable carrier. 
     
     
         68 . A method for modulating a growth inhibitory effect of paclitaxel on a carcinoma which comprises contacting the carcinoma with paclitaxel and an effective amount of digitoxin, which results in a synergistic effect of the paclitaxel on the carcinoma, and optionally an additional chemopreventive or chemotherapeutic agent which is selected from the group consisting of an ethyl acetate extract of black cohosh and actein. 
     
     
         69 . The method of  claim 68  wherein the amount Of digitoxin and paclitaxel are at least 0.01 μg/ml digitoxin and 1 nM paclitaxel. 
     
     
         70 . The method of  claim 68  wherein the amount of digitoxin and paclitaxel are at least 0.05 μg/ml digitoxin and 0.025 nM paclitaxel. 
     
     
         71 . A method for inhibiting the progression or development of breast cancer in vivo, comprising administering to a subject a composition comprising an extract of black cohosh comprising a triterpene glycoside, and optionally an effective amount of at least one additional chemopreventive or chemotherapeutic agent. 
     
     
         72 . A method for inhibiting the progression or development of breast cancer in vivo, comprising administering to a subject a composition comprising actein, and optionally an effective amount of at least one additional chemopreventive or chemotherapeutic agent.