- Email: [email protected]
Digitalis; impinges on more than just the (ion-) pump
Medical Hypotheses (2002) 59(6), 781–782 ª 2002 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0306-9877(02)00334-1, available online at http://www.idealibrary.com
Digitalis; impinges on more than just the (ion-) pump J. Haux Department of Oncology, St. Olav’s University Hospital, Trondheim, Norway
Summary Some forms of digitalis, such as digitoxin, inhibits proliferation and induces apoptosis in cancer cells in clinically relevant concentrations. Recently, it has been demonstrated that digitalis, in addition to inhibiting the Naþ /Kþ -ATPase, also signals through the pathways of the epidermal growth factor receptor (EGFR). Digitalis has complex dose-dependent mechanisms of action involving many signaling systems and the relevance of this for the anticancer effects are discussed. ª 2002 Elsevier Science Ltd. All rights reserved.
William Withering, more than 200 years ago, established the use of digitalis for cardiac congestion and still today many cardiac patients benefit from this. Some forms of digitalis (chemically cardenolides and bufadienolides) also have anticancer effects in vitro and in vivo (1–5). The well known and accepted mode of action of digitalis is inhibition of the ubiquitous plasma membrane Naþ /Kþ -ATPase that lead to increased intracellular Ca2þ ion concentrations and strengthened heart beat. Ca2þ ions also play pivotal roles in many signaling pathways including those regulating apoptosis. Still it has been difficult to explain the anticancer effects of digitalis in the many diverse cancer cell lines in concentrations sparing normal cells (1–4). Among the most common perturbations in malignant transformed cells are overexpression and/or mutations of growth factor tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR) and/or proteins in their signaling pathways. New drugs that block such signals are already in use in oncology and show promising re-
Received 18 June 2002 Accepted 15 July 2002 Correspondence to: J. Haux, Department of Oncology, St. Olav’s University Hospital, N-7006 Trondheim, Norway. Tel.: +47-73867830; Fax: +47-956-11-184 E-mail: [email protected]
sults. Now it has been shown that digitalis also signals through these pathways and it is proposed that the Naþ / Kþ ATPase have two distinct roles; the well known as an ion pump and in addition as a protein–protein signal transducer (6). The latter is a novel discovery that directly couples digitalis to several signaling pathways that regulate apoptosis. Digitalis starts such signal cascades even before ion changes are detected (6). The effects on the cell cycle including accumulation of sensitive cells in the G2 M phase and increased cell death, also through apoptosis, indicate that digitalis may stimulate susceptible cells to enter the cell cycle but concomitant inhibitory signals result in cell death (1–3). Digitalis also regulates one of the most potent angiogenesis promoting substances known, fibroblast growth factor-2 (FGF-2), and digitalis may also inhibit activation of the transcription factor NF-kB, both of which are relevant targets for anticancer drugs. Digitalis has complex dosedependent mechanisms of action; lower concentrations may induce transcription of survival genes whereas higher concentrations can induce cell death by caspase activation and even higher concentrations induce cell death through necrosis due to heavily disrupted ion homeostasis (1–4,6). Some of the same concentration dependent actions have been shown for other phenolic compounds of plant origin (7). Apparently, the modes of action of digitalis are extremely complex as several signaling pathways are targeted simultaneously. This might be an efficient way to induce cell death and impede the cancer cells to develop
781
782 Haux
resistance compared to when just one major signaling pathway is blocked. Digitalis in the form of digitoxin seems to have a favorable profile by inducing cell death in an array of cancer cells within the upper part of therapeutic plasma concentration (1,2,4,5). Thus, it is much more to learn about the modes of action of digitalis on the molecular level and probably also concerning physiological effects in health and disease.
REFERENCES 1. Haux J. Digitoxin is a potential anticancer agent for several types of cancer. Med Hypotheses 1999; 53: 543–548, doi:10.1054/mehy.1999.0985. 2. Haux J., Solheim O., Isaksen T., Angelsen A. Digitoxin, in non-toxic concentrations, inhibits proliferation and induces €r cell death in prostate cancer cell lines. Z Onkol (Zeitschrift fu Onkologie) 2000; 32: 11–16.
Medical Hypotheses (2002) 59(6), 781–782
3. McConkey D. J., Lin Y., Nutt L. K., Ozel H. Z., Newman R. A. Cardiac glycosides stimulate Ca2þ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells. Cancer Res 2000; 60: 3807–3812. 4. Johansson S., Lindholm P., Gullbo J., Larsson R., Bohlin L., Claeson P. Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells. Anticancer Drugs 2001; 12: 475–483. 5. Haux J., Klepp O., Spigset O., Tretli S. Digitoxin medication and cancer; case control and internal dose–response studies. BMC Cancer 2001; 1: 11. 6. Liu J., Tian J., Haas M., Shapiro J. I., Askari A., Xie Z. Ouabain interaction with cardiac Naþ /Kþ -ATPase initiates signal cascades independent of changes in intracellular Naþ and Ca2þ concentrations. J Biol Chem 2000; 275: 27838– 27844. 7. Kong A. N., Yu R., Chen C., Mandlekar S., Primiano T. Signal transduction events elicited by natural products: role of MAPK and caspase pathways in homeostatic response and induction of apoptosis. Arch Pharm Res 2000; 23: 1–16.
ª 2002 Elsevier Science Ltd. All rights reserved.
Digitalis; impinges on more than just the (ion-) pump J. Haux Department of Oncology, St. Olav’s University Hospital, Trondheim, Norway
Summary Some forms of digitalis, such as digitoxin, inhibits proliferation and induces apoptosis in cancer cells in clinically relevant concentrations. Recently, it has been demonstrated that digitalis, in addition to inhibiting the Naþ /Kþ -ATPase, also signals through the pathways of the epidermal growth factor receptor (EGFR). Digitalis has complex dose-dependent mechanisms of action involving many signaling systems and the relevance of this for the anticancer effects are discussed. ª 2002 Elsevier Science Ltd. All rights reserved.
William Withering, more than 200 years ago, established the use of digitalis for cardiac congestion and still today many cardiac patients benefit from this. Some forms of digitalis (chemically cardenolides and bufadienolides) also have anticancer effects in vitro and in vivo (1–5). The well known and accepted mode of action of digitalis is inhibition of the ubiquitous plasma membrane Naþ /Kþ -ATPase that lead to increased intracellular Ca2þ ion concentrations and strengthened heart beat. Ca2þ ions also play pivotal roles in many signaling pathways including those regulating apoptosis. Still it has been difficult to explain the anticancer effects of digitalis in the many diverse cancer cell lines in concentrations sparing normal cells (1–4). Among the most common perturbations in malignant transformed cells are overexpression and/or mutations of growth factor tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), platelet derived growth factor receptor (PDGFR) and/or proteins in their signaling pathways. New drugs that block such signals are already in use in oncology and show promising re-
Received 18 June 2002 Accepted 15 July 2002 Correspondence to: J. Haux, Department of Oncology, St. Olav’s University Hospital, N-7006 Trondheim, Norway. Tel.: +47-73867830; Fax: +47-956-11-184 E-mail: [email protected]
sults. Now it has been shown that digitalis also signals through these pathways and it is proposed that the Naþ / Kþ ATPase have two distinct roles; the well known as an ion pump and in addition as a protein–protein signal transducer (6). The latter is a novel discovery that directly couples digitalis to several signaling pathways that regulate apoptosis. Digitalis starts such signal cascades even before ion changes are detected (6). The effects on the cell cycle including accumulation of sensitive cells in the G2 M phase and increased cell death, also through apoptosis, indicate that digitalis may stimulate susceptible cells to enter the cell cycle but concomitant inhibitory signals result in cell death (1–3). Digitalis also regulates one of the most potent angiogenesis promoting substances known, fibroblast growth factor-2 (FGF-2), and digitalis may also inhibit activation of the transcription factor NF-kB, both of which are relevant targets for anticancer drugs. Digitalis has complex dosedependent mechanisms of action; lower concentrations may induce transcription of survival genes whereas higher concentrations can induce cell death by caspase activation and even higher concentrations induce cell death through necrosis due to heavily disrupted ion homeostasis (1–4,6). Some of the same concentration dependent actions have been shown for other phenolic compounds of plant origin (7). Apparently, the modes of action of digitalis are extremely complex as several signaling pathways are targeted simultaneously. This might be an efficient way to induce cell death and impede the cancer cells to develop
781
782 Haux
resistance compared to when just one major signaling pathway is blocked. Digitalis in the form of digitoxin seems to have a favorable profile by inducing cell death in an array of cancer cells within the upper part of therapeutic plasma concentration (1,2,4,5). Thus, it is much more to learn about the modes of action of digitalis on the molecular level and probably also concerning physiological effects in health and disease.
REFERENCES 1. Haux J. Digitoxin is a potential anticancer agent for several types of cancer. Med Hypotheses 1999; 53: 543–548, doi:10.1054/mehy.1999.0985. 2. Haux J., Solheim O., Isaksen T., Angelsen A. Digitoxin, in non-toxic concentrations, inhibits proliferation and induces €r cell death in prostate cancer cell lines. Z Onkol (Zeitschrift fu Onkologie) 2000; 32: 11–16.
Medical Hypotheses (2002) 59(6), 781–782
3. McConkey D. J., Lin Y., Nutt L. K., Ozel H. Z., Newman R. A. Cardiac glycosides stimulate Ca2þ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells. Cancer Res 2000; 60: 3807–3812. 4. Johansson S., Lindholm P., Gullbo J., Larsson R., Bohlin L., Claeson P. Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells. Anticancer Drugs 2001; 12: 475–483. 5. Haux J., Klepp O., Spigset O., Tretli S. Digitoxin medication and cancer; case control and internal dose–response studies. BMC Cancer 2001; 1: 11. 6. Liu J., Tian J., Haas M., Shapiro J. I., Askari A., Xie Z. Ouabain interaction with cardiac Naþ /Kþ -ATPase initiates signal cascades independent of changes in intracellular Naþ and Ca2þ concentrations. J Biol Chem 2000; 275: 27838– 27844. 7. Kong A. N., Yu R., Chen C., Mandlekar S., Primiano T. Signal transduction events elicited by natural products: role of MAPK and caspase pathways in homeostatic response and induction of apoptosis. Arch Pharm Res 2000; 23: 1–16.
ª 2002 Elsevier Science Ltd. All rights reserved.