Paracelsus Paradox and Drug Repurposing for Cancer

Tomas Koltai (Former Director of the Centro Gallego Hospital of Buenos Aires, Buenos Aires, Argentina)

Article ID: 3649

DOI: https://doi.org/10.30564/jor.v3i2.3649

Abstract


Dose is one of the parameters that any pharmacologist seriously considers when studying the effects of a drug. If the necessary dose to achieve a desired pharmacological effect is in a toxic or very toxic range for human use, the drug will probably fall out from further research. The concentration that a drug can reach at its target organ or cell is a direct consequence of the administered dose and its pharmacodynamic properties. Basic researchers investigate at the cellular level or eventually with xenografts. They use different concentrations of the drug in order to determine its cellular effects. However, in many cases, these concentrations require doses that are in the toxic range or well beyond any clinically achievable level. Therefore, in these cases, research is in the realm of Toxicology rather than therapeutics. This paper will show some examples about this exercise in futility which is time and resource consuming but that pullulates the pages of many prestigious journals. Many seasoned researchers seem to have forgotten the Paracelsus Paradox.


Keywords


Dose bias; Drug repurposing; Cancer; Metformin; Statins

Full Text:

PDF

References


[1] Björkhem-Bergman, L., Lindh, J. D., & Bergman, P. (2011). What is a relevant statin concentration in cell experiments claiming pleiotropic effects?. British journal of clinical pharmacology, 72(1), 164.

[2] Keskitalo, J. E., Pasanen, M. K., Neuvonen, P. J., & Niemi, M. (2009). Different effects of the ABCG2 c. 421C> A SNP on the pharmacokinetics of fluvastatin, pravastatin and simvastatin. Pharmacogenomics, 10(10), 1617-1624.

[3] Spampanato, C., De Maria, S., Sarnataro, M., Giordano, E., Zanfardino, M., Baiano, S., ... & Morelli, F. (2012). Simvastatin inhibits cancer cell growth by inducing apoptosis correlated to activation of Bax and down-regulation of BCL-2 gene expression. International journal of oncology, 40(4), 935-941.

[4] Hoque, A., Chen, H., & Xu, X. C. (2008). Statin induces apoptosis and cell growth arrest in prostate cancer cells. Cancer Epidemiology and Prevention Biomarkers, 17(1), 88-94.

[5] Hamidi, M., Zarei, N., & Shahbazi, M. A. (2009). A simple and sensitive HPLC-UV method for quantitation of lovastatin in human plasma: application to a bioequivalence study. Biological and Pharmaceutical Bulletin, 32(9), 1600-1603.

[6] Sidaway, J., Wang, Y., Marsden, A. M., Orton, T. C., Westwood, F. R., Azuma, C. T., & Scott, R. C. (2009). Statin-induced myopathy in the rat: relationship between systemic exposure, muscle exposure and myopathy. Xenobiotica, 39(1), 90-98.

[7] Zhuang, L., Kim, J., Adam, R. M., Solomon, K. R., & Freeman, M. R. (2005). Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts. The Journal of clinical investigation, 115(4), 959-968.

[8] Wong, W. W., Dimitroulakos, J., Minden, M. D., & Penn, L. Z. (2002). HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia, 16(4), 508-519.

[9] Hindler, K., Cleeland, C. S., Rivera, E., & Collard, C. D. (2006). The role of statins in cancer therapy. The oncologist, 11(3), 306-315.

[10] Dimitroulakos, J., Lily, Y. Y., Benzaquen, M., Moore, M. J., Kamel-Reid, S., Freedman, M. H., ... & Penn, L. Z. (2001). Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications. Clinical cancer research, 7(1), 158-167.

[11] G Vallianou, N., Kostantinou, A., Kougias, M., & Kazazis, C. (2014). Statins and cancer. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 14(5), 706-712.

[12] Cafforio, P., Dammacco, F., Gernone, A., & Silvestris, F. (2005). Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. Carcinogenesis, 26(5), 883-891.

[13] Palko-Łabuz, A., Środa-Pomianek, K., Wesołowska, O., Kostrzewa-Susłow, E., Uryga, A., & Michalak, K. (2019). MDR reversal and pro-apoptotic effects of statins and statins combined with flavonoids in colon cancer cells. Biomedicine & Pharmacotherapy, 109, 1511-1522.

[14] 108.- Sun, Q., Arnold, R. S., Q Sun, C., & A Petros, J. (2015). A mitochondrial DNA mutation influences the apoptotic effect of statins on prostate cancer. The Prostate, 75(16), 1916-1925.

[15] Wood, W. G., Igbavboa, U., Muller, W. E., & Eckert, G. P. (2013). Statins, Bcl-2, and apoptosis: cell death or cell protection?. Molecular neurobiology, 48(2), 308-314.

[16] Gordon, J. A., Midha, A., Szeitz, A., Ghaffari, M., Adomat, H. H., Guo, Y., ... & Cox, M. E. (2016). Oral simvastatin administration delays castration-resistant progression and reduces intratumoral steroidogenesis of LNCaP prostate cancer xenografts. Prostate cancer and prostatic diseases, 19(1), 21-27.

[17] García-Ruiz, C., Morales, A., & C Fernandez-Checa, J. (2012). Statins and protein prenylation in cancer cell biology and therapy. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 12(4), 303-315.

[18] Dai, Y., Khanna, P., Chen, S., Pei, X. Y., Dent, P., & Grant, S. (2007). Statins synergistically potentiate 7-hydroxystaurosporine (UCN-01) lethality in human leukemia and myeloma cells by disrupting Ras farnesylation and activation. Blood, 109(10), 4415-4423.

[19] Ghittoni, R., Patrussi, L., Pirozzi, K., Pellegrini, M., Lazzerini, P. E., Capecchi, P. L., ... & Baldari, C. T. (2005). Simvastatin inhibits T‐cell activation by selectively impairing the function of Ras superfamily GTPases. The FASEB journal, 19(6), 1-24.

[20] Graaf, M. R., Richel, D. J., van Noorden, C. J., & Guchelaar, H. J. (2004). Effects of statins and farnesyltransferase inhibitors on the development and progression of cancer. Cancer treatment reviews, 30(7), 609-641.

[21] Cho, K. J., Hill, M. M., Chigurupati, S., Du, G., Parton, R. G., & Hancock, J. F. (2011). Therapeutic levels of the hydroxmethylglutaryl-coenzyme A reductase inhibitor lovastatin activate ras signaling via phospholipase D2. Molecular and Cellular Biology, 31(6), 1110-1120.

[22] Evans, J. M., Donnelly, L. A., Emslie-Smith, A. M., Alessi, D. R., & Morris, A. D. (2005). Metformin and reduced risk of cancer in diabetic patients. Bmj, 330(7503), 1304-1305.

[23] Drug Repurposing in Cancer Therapy. (2020), Academic Press. Elsevier. Editors To, K.K.W. and Cho, W.C.S. Page 124. Chapter 5 by Kahn, H.J., Rohondia, S.O,, Othman Ahmed, Z.S., Zalavadiya, N., Ping Dou, Q.

[24] Lee, S. H., & Kwon, K. I. (2004). Pharmacokinetic-pharmacodynamic modeling for the relationship between glucose-lowering effect and plasma concentration of metformin in volunteers. Archives of pharmacal research, 27(7), 806-810.

[25] He, L., & Wondisford, F. E. (2015). Metformin action: concentrations matter. Cell metabolism, 21(2), 159-162.

[26] Wilcock, C., & Bailey, C. J. (1994). Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica, 24(1), 49-57.

[27] Kajbaf, F., De Broe, M. E., & Lalau, J. D. (2016). Therapeutic concentrations of metformin: a systematic review. Clinical pharmacokinetics, 55(4), 439-459.

[28] Dell'Aglio, D. M., Perino, L. J., Kazzi, Z., Abramson, J., Schwartz, M. D., & Morgan, B. W. (2009). Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature. Annals of emergency medicine, 54(6), 818-823.

[29] Kajbaf, F., & Lalau, J. D. (2013). The prognostic value of blood pH and lactate and metformin concentrations in severe metformin-associated lactic acidosis. BMC Pharmacology and Toxicology, 14(1), 1-5.

[30] Zhang, Y., Guan, M., Zheng, Z., Zhang, Q., Gao, F., & Xue, Y. (2013). Effects of metformin on CD133+ colorectal cancer cells in diabetic patients. PLoS One, 8(11), e81264.

[31] Kim, M. Y., Kim, Y. S., Kim, M., Choi, M. Y., Roh, G. S., Lee, D. H., ... & Choi, W. S. (2019). Metformin inhibits cervical cancer cell proliferation via decreased AMPK O-GlcNAcylation. Animal cells and systems, 23(4), 302-309.

[32] Jang, J. H., Sung, E. G., Song, I. H., Lee, T. J., & Kim, J. Y. (2020). Metformin induces caspase-dependent and caspase-independent apoptosis in human bladder cancer T24 cells. Anti-cancer drugs, 31(7), 655–662. https://doi.org/10.1097/CAD.0000000000000966.

[33] Griss, T., Vincent, E. E., Egnatchik, R., Chen, J., Ma, E. H., Faubert, B., ... & Jones, R. G. (2015). Metformin antagonizes cancer cell proliferation by suppressing mitochondrial-dependent biosynthesis. PLoS biology, 13(12), e1002309.

[34] Clark, R., & Lee, S. H. (2016). Anticancer properties of capsaicin against human cancer. Anticancer research, 36(3), 837-843.

[35] Mori, A., Lehmann, S., O'Kelly, J., Kumagai, T., Desmond, J. C., Pervan, M., ... & Koeffler, H. P. (2006). Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells. Cancer research, 66(6), 3222-3229.

[36] Lin, C. H., Lu, W. C., Wang, C. W., Chan, Y. C., & Chen, M. K. (2013). Capsaicin induces cell cycle arrest and apoptosis in human KB cancer cells. BMC complementary and alternative medicine, 13(1), 1-9.

[37] Chow, J., Norng, M., Zhang, J., & Chai, J. (2007). TRPV6 mediates capsaicin-induced apoptosis in gastric cancer cells—Mechanisms behind a possible new “hot” cancer treatment. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1773(4), 565-576.

[38] Zhang, R., Humphreys, I., Sahu, R. P., Shi, Y., & Srivastava, S. K. (2008). In vitro and in vivo induction of apoptosis by capsaicin in pancreatic cancer cells is mediated through ROS generation and mitochondrial death pathway. Apoptosis, 13(12), 1465-1478.

[39] Thoennissen, N. H., O'kelly, J., Lu, D., Iwanski, G. B., La, D. T., Abbassi, S., ... & Koeffler, H. P. (2010). Capsaicin causes cell-cycle arrest and apoptosis in ER-positive and-negative breast cancer cells by modulating the EGFR/HER-2 pathway. Oncogene, 29(2), 285-296.

[40] Chou, C. C., Wu, Y. C., Wang, Y. F., Chou, M. J., Kuo, S. J., & Chen, D. R. (2009). Capsaicin-induced apoptosis in human breast cancer MCF-7 cells through caspase-independent pathway. Oncology reports, 21(3), 665-671.

[41] Lee, S. H., Richardson, R. L., Dashwood, R. H., & Baek, S. J. (2012). Capsaicin represses transcriptional activity of β-catenin in human colorectal cancer cells. The Journal of nutritional biochemistry, 23(6), 646-655.

[42] Lu, H. F., Chen, Y. L., Yang, J. S., Yang, Y. Y., Liu, J. Y., Hsu, S. C., ... & Chung, J. G. (2010). Antitumor activity of capsaicin on human colon cancer cells in vitro and colo 205 tumor xenografts in vivo. Journal of agricultural and food chemistry, 58(24), 12999-13005.

[43] Lau, J. K., Brown, K. C., Dom, A. M., Witte, T. R., Thornhill, B. A., Crabtree, C. M., ... & Dasgupta, P. (2014). Capsaicin induces apoptosis in human small cell lung cancer via the TRPV6 receptor and the calpain pathway. Apoptosis, 19(8), 1190-1201.

[44] Yang, J., Li, T. Z., Xu, G. H., Luo, B. B., Chen, Y. X., & Zhang, T. (2013). Low-concentration capsaicin promotes colorectal cancer metastasis by triggering ROS production and modulating Akt/mTOR and STAT-3 pathways. Neoplasma, 60(4), 364-372.

[45] Liu, T., Wang, G., Tao, H. et al. Capsaicin mediates caspases activation and induces apoptosis through P38 and JNK MAPK pathways in human renal carcinoma. BMC Cancer 16, 790 (2016). https://doi.org/10.1186/s12885-016-2831-y.

[46] Reilly, C. A., Crouch, D. J., Yost, G. S., & Fatah, A. A. (2002). Determination of capsaicin, nonivamide, and dihydrocapsaicin in blood and tissue by liquid chromatography-tandem mass spectrometry. Journal of analytical toxicology, 26(6), 313-319.

[47] Suresh, D., & Srinivasan, K. (2010). Tissue distribution & elimination of capsaicin, piperine & curcumin following oral intake in rats. Indian Journal of Medical Research, 131(5).

[48] Hartley, T., Stevens, B., Ahuja, K. D., & Ball, M. J. (2013). Development and experimental application of an hplc procedure for the determination of capsaicin and dihydrocapsaicin in serum samples from human subjects. Indian Journal of Clinical Biochemistry, 28(4), 329-335.

[49] Koltai, T. (2015). Fenofibrate in cancer: mechanisms involved in anticancer activity. F1000Research, 4(55), 55.

[50] Reiss, K., Urbanska, K., DelValle, L., & Mencel, P. J. (2008). PPARα agonist fenofibrate inhibits IGF-I-mediated growth and DNA repair responses and sensitizes human glioblastoma cells to cisplatin. Journal of Clinical Oncology, 26(15_suppl), 13020-13020.

[51] Drukala, J., Urbanska, K., Wilk, A., Grabacka, M., Wybieralska, E., Del Valle, L., ... & Reiss, K. (2010). ROS accumulation and IGF-IR inhibition contribute to fenofibrate/PPARα-mediated inhibition of glioma cell motility in vitro. Molecular cancer, 9(1), 1-15.

[52] Giordano, A., & Macaluso, M. (2012). Fenofibrate triggers apoptosis of glioblastoma cells in vitro: New insights for therapy. Cell Cycle, 11(17), 3154-3154.

[53] Wilk, A., Urbanska, K., Grabacka, M., Mullinax, J., Marcinkiewicz, C., Impastato, D., ... & Reiss, K. (2012). Fenofibrate-induced nuclear translocation of FoxO3A triggers Bim-mediated apoptosis in glioblastoma cells in vitro. Cell cycle, 11(14), 2660-2671.

[54] Wilk, A. M., Zapata, A. M., Mullinax, J. R., Wyczechowska, D. D., & Reiss, K. (2013). PPAR alpha independent effect of fenofibrate on glioblastoma cancer metabolism.

[55] Binello, E., Mormone, E., Emdad, L., Kothari, H., & Germano, I. M. (2014). Characterization of fenofibrate-mediated anti-proliferative pro-apoptotic effects on high-grade gliomas and anti-invasive effects on glioma stem cells. Journal of neuro-oncology, 117(2), 225-234.

[56] Han, D., Wei, W., Chen, X., Zhang, Y., Wang, Y., Zhang, J., ... & You, Y. (2015). NF-κB/RelA-PKM2 mediates inhibition of glycolysis by fenofibrate in glioblastoma cells. Oncotarget, 6(28), 26119.

[57] Grabacka, M. M., Wilk, A., Antonczyk, A., Banks, P., Walczyk-Tytko, E., Dean, M., ... & Reiss, K. (2016). Fenofibrate induces ketone body production in melanoma and glioblastoma cells. Frontiers in endocrinology, 7, 5.

[58] Kast, R. E., Hill, Q. A., Wion, D., Mellstedt, H., Focosi, D., Karpel-Massler, G., ... & Halatsch, M. E. (2017). Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin. Tumor Biology, 39(5), 1010428317699797.

[59] Haynes, H. R., White, P., Hares, K. M., Redondo, J., Kemp, K. C., Singleton, W. G., ... & Kurian, K. M. (2017). The transcription factor PPARα is overexpressed and is associated with a favourable prognosis in IDH‐wildtype primary glioblastoma. Histopathology, 70(7), 1030-1043.

[60] Stalinska, J., Zimolag, E., Pianovich, N. A., Zapata, A., Lassak, A., Rak, M., ... & Reiss, K. (2019). Chemically Modified Variants of Fenofibrate with Antiglioblastoma Potential. Translational oncology, 12(7), 895-907.

[61] Grabacka, M., Waligorski, P., Zapata, A., Blake, D. A., Wyczechowska, D., Wilk, A., ... & Reiss, K. (2015). Fenofibrate subcellular distribution as a rationale for the intracranial delivery through biodegradable carrier. Journal of physiology and pharmacology: an official journal of the Polish Physiological Society, 66(2), 233.

[62] Harguindey, S., Polo Orozco, J., Alfarouk, K. O., & Devesa, J. (2019). Hydrogen ion dynamics of cancer and a new molecular, biochemical and metabolic approach to the etiopathogenesis and treatment of brain malignancies. International journal of molecular sciences, 20(17), 4278.

[63] Saller, R., Brignoli, R., Melzer, J., & Meier, R. (2008). An updated systematic review with meta-analysis for the clinical evidence of silymarin. Complementary Medicine Research, 15(1), 9-20.

[64] Wu, J.W., Lin, L. C., Hung, S. C., Chi, C.W., Tsai, T H. (2007). Analysis of silibinin in rat plasma and bile for hepatobiliary excretion and oral bioavailability application. J. Pharm. Biomed. Anal. 45: 635-641. doi: https://doi.org/10.1016/j.jpba.2007.06.026.

[65] Fraschini, F., Demartini, G., Esposti, D. (2002). Pharmacology of silymarin. Clinical drug investigation, 22(1), 51-65. doi: https://doi.org/10.2165/00044011-200222010-00007.

[66] Janiak, B., Kessler, B., Kunz, W., & Schnieders, B. (1973). Die wirkung von silymarin auf gehalt und function einiger durch einwirkung von tetrachlorkohlenstoff bzw. Halothan beeinflussten mikrosomalen Leberenzyme. Arzneimittelforschung, 23, 1322-6. PMID: 4801229.

[67] Lorenz, D., Lucker, P. W., Mennicke, W.H., Wetzelsberger, N. (1984). Pharmacokinetic studies with silymarin in human serum and bile. Methods find. Exp Clin Pharmacol, 6, 655-661. PMID: 6513680.

[68] Beckmann‐Knopp, S., Rietbrock, S., Weyhenmeyer, R., Böcker, R. H., Beckurts, K. T., Lang, W., ... & Fuhr, U. (2000). Inhibitory effects of silibinin on cytochrome P‐450 enzymes in human liver microsomes. Pharmacology & toxicology, 86(6), 250-256. https://doi.org/10.1111/j.0901-9928.2000.860602.x.

[69] Gatti, G., & Perucca, E. (1994). Plasma concentrations of free and conjugated silybin after oral intake of a silybin-phosphatidylcholine complex (silipide) in healthy volunteers. International journal of clinical pharmacology and therapeutics, 32(11), 614-617. PMID: 7874377 .

[70] Lorenz, D., Lücker, P. W., Mennicke, W. H., & Wetzelsberger, N. (1984). Pharmacokinetic studies with silymarin in human serum and bile. Methods and findings in experimental and clinical pharmacology, 6(10), 655-661. PMID: 6513680.

[71] Filburn, C. R., Kettenacker, R., & Griffin, D. W. (2007). Bioavailability of a silybin–phosphatidylcholine complex in dogs. Journal of veterinary pharmacology and therapeutics, 30(2), 132-138. https://doi.org/10.1111/j.1365-2885.2007.00834.x.

[72] Morazzoni, P., Montalbetti, A., Malandrino, S., & Pifferi, G. (1993). Comparative pharmacokinetics of silipide and silymarin in rats. European journal of drug metabolism and pharmacokinetics, 18(3), 289-297. doi: https://doi.org/10.1007/BF03188811.


Refbacks

  • There are currently no refbacks.
Copyright © 2021 Author(s)


Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.