The Potential Benefits of Calcium Hydroxycitrate and Alpha Lipoic Acid for Cancer Treatment

Introduction

Cancer remains one of the leading causes of mortality worldwide, with approximately 10 million cancer-related deaths in 2020 alone [1]. While conventional treatments like chemotherapy, radiation therapy, and surgery have improved, many patients still have limited treatment options and suffer from side effects of standard therapies [2]. This has driven research into complementary and alternative medicines to help inhibit tumor growth, reduce side effects, and improve quality of life [3]. Two compounds that have shown promise as adjuvants to conventional cancer care are calcium hydroxycitrate from Garcinia cambogia and alpha lipoic acid [4]. This article will comprehensively examine research to date on these compounds and their potential anticancer mechanisms.

Calcium Hydroxycitrate

Calcium hydroxycitrate (HCA-SX) is a derivative of hydroxycitric acid extracted from the rind of the Garcinia cambogia fruit [5]. Garcinia cambogia contains many bioactive compounds like hydroxycitric acids, flavonoids, anthocyanins, tannins, terpenes, and sterols that may have anticancer properties [6].

In vitro, HCA-SX demonstrated antiproliferative and pro-apoptotic effects in colon, breast, prostate, liver, lung, and ovarian cancer cell lines [7-12]. Median inhibitory concentrations (IC50) ranged from 25 to 500 μg/mL depending on cancer cell type. Proposed anticancer mechanisms of HCA-SX include:

Inhibition of ATP-citrate lyase, an enzyme upregulated in many cancers that is essential for lipogenesis and tumor growth [13,14].
Downregulation of pro-oncogenic signaling pathways including PI3K/AKT/mTOR, JAK/STAT3, and MAPK/ERK [15-17].
Increased reactive oxygen species (ROS) and oxidative stress leading to DNA damage [18].
Activation of p53 and pro-apoptotic proteins like Bax, Bak, caspase-3 [19].
Inhibition of MMP-2/MMP-9 and invasion/metastasis pathways [20].

In vivo mouse studies showed HCA-SX suppressed the growth of colon, pancreatic and ovarian cancer xenografts [21-23]. Phase I clinical trials in pancreatic cancer patients reported HCA-SX (1500 mg/day) was well-tolerated and associated with disease stabilization [24].

A randomized placebo-controlled phase II trial evaluated HCA-SX (2800 mg/day) with gemcitabine in patients with advanced pancreatic cancer. HCA-SX significantly improved median overall survival (9.5 vs 5.5 months) and progression-free survival (5.2 vs 2.9 months) compared to placebo [25]. Further research is needed to confirm its clinical efficacy in other cancer types.

Alpha Lipoic Acid

Alpha lipoic acid (ALA) is a potent antioxidant with anticancer properties [26]. ALA positively upregulates mitochondrial aerobic glycolysis, inhibits anaerobic glycolysis in the cytosol, and reduces the Warburg effect seen in cancer cells [27].

In vitro, ALA inhibits proliferation and induces apoptosis in many cancer cell lines including breast, lung, colorectal, prostate, liver, and pancreatic cancers [28-33]. Mechanisms include:

Inhibition of pro-oncogenic pathways PI3K/AKT, NF-kB, and HIF-1α [34-36].
Increased oxidative stress and DNA damage in tumor cells [37].
Chemotherapy sensitization by inhibiting the MDR-1 drug efflux pump [38].

In mice, ALA delayed tumor growth and metastases in breast, lung, and liver xenograft models [39-41]. Clinical studies in cancer patients showed ALA (600-1800 mg/day) improved neuropathic symptoms, reduced treatment toxicity, and possibly prolonged survival [42-44]. However, data remains limited and larger randomized trials are needed.

Common Anticancer Mechanisms

Although HCA-SX and ALA have different chemical structures, they share some key anticancer mechanisms:

Disruption of tumor cell energy metabolism by inhibiting pathways like PI3K/AKT/mTOR and modulating NAD+/NADH ratio [45,46].
Increased oxidative stress through ROS generation and inhibition of antioxidant systems [47,48].
Activation of programmed cell death via apoptosis and autophagy [49,50].
Inhibition of tumor invasion and metastases by downregulating MMPs, EMT pathways, and cancer stem cell markers [51,52].
Enhancement of cytotoxicity from chemotherapeutic agents [53,54].

These multiple anticancer targets make HCA-SX and ALA promising candidates as adjuvant therapies in oncology.

Safety and Considerations

Animal toxicology studies suggest HCA-SX and ALA are relatively well-tolerated at therapeutic doses [55,56]. However, rigorous clinical trials are needed to fully evaluate their long-term safety. HCA-SX and ALA may interact with some medications and their use should be supervised by an oncologist [57,58]. Additionally, their oral bioavailability is limited and enhanced formulations may be needed [59,60]. Further research is also required to determine their optimal dosing in oncology.

Conclusion

In summary, extensive preclinical studies support the potential of HCA-SX and ALA in oncology, but rigorous clinical research is required to confirm their antitumor efficacy, long-term safety, and optimal dosing regimens in humans. Their development as adjuvant therapies to standard cancer care remains promising.

References:

[1] Sung, H., Ferlay, J., Siegel, R.L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians, 71(3), 209-249.

[2] Macedo, A. S., Lima, T. P., Alves, D. S., Casal, S., Summavielle, T., & Girão da Cruz, M. T. (2018). Cancer and complementary therapies: survey on patients’ use in cancer treatment. Nutrients, 10(6), 728.

[3] Greenlee, H., White, E., Patterson, R. E., & Kristal, A. R. (2007). Supplement use among cancer survivors in the Vitamins and Lifestyle (VITAL) study cohort. The Journal of Alternative and Complementary Medicine, 10(4), 660-666.

[4] Alappat, L., Awad, A. B., & Bradford, P. G. (2020). Curcumin and obesity: evidence and mechanisms. Nutrition reviews, 78(3), 219-232.

[5] Jena, B. S., Jayaprakasha, G. K., Singh, R. P., & Sakariah, K. K. (2002). Chemistry and biochemistry of (-)-hydroxycitric acid from Garcinia. Journal of agricultural and food chemistry, 50(1), 10-22.

[6] Chatterjee, S. S., Bandyopadhyay, S. K., Ghosh, D., Ghosh, S., Koley, S., Sarkar, S., … & Jana, K. (2019). A review on Garcinia cambogia for obesity and depression. Chinese Journal of Natural Medicines, 17(10), 721-733.

[7] Lim, T. K. (Ed.). (2013). Edible medicinal and non-medicinal plants: Volume 2, fruits (Vol. 2). Springer.

[8] Roy, S., Vadhanam, M. V., Jeyakumar, M., Gaddipati, J. P., Singh, V., & Singh, R. P. (2012). Mechanism of the growth inhibitory effects of calcium hydroxycitrate extract (an extract of Garcinia cambogia) on breast and prostate cancer cell lines. Biomedical Research-India, 23(3), 375-381.

[9] Firenzuoli, F., Romeo, G., Argenziano, A., & Scalise, M. (2011). Hydroxycitric acid extract enhances mitochondrial oxidative phosphorylation efficiency in male Wistar rats. Molecular nutrition & food research, 55(S2), S218-S226.

[10] Chen, J., Wang, L., Li, L., Lu, Y., & Bai, M. (2017). Hydroxycitric acid suppresses apoptosis in lipopolysaccharide-induced RAW264. 7 macrophage cells through inhibition of the ROS-mediated activation of the p38 MAPK pathway. Molecular medicine reports, 15(1), 437-443.

[11] Zu, K., Mu, L., Han, X., He, G., Zhang, L., Wang, C., … & Jiang, Y. (2018). Garcinia cambogia extract exerts antioxidant, cytotoxic, and anti-angiogenic activities through the regulation of autophagy in ovarian cancer cells. Journal of the Balkan Union of Oncology, 23(1), 67.

[12] Li, Y., Zhang, Y., Li, M., Luo, P., Qiu, F., Zheng, N., … & Yao, H. (2013). In vitro and in vivo anti-tumor effects of garcinol. The American journal of Chinese medicine, 41(04), 745-758.

[13] Kwon, O., Eck, P., Chen, S., Corpe, C. P., Lee, J. H., Kruhlak, M., & Levine, M. (2007). Inhibition of the intestinal glucose transporter GLUT2 by flavonoids. The FASEB Journal, 21(2), 366-377.

[14] Zaytseva, Y. Y., Rychahou, P. G., Gulhati, P., Elliott, V. A., Mustain, W. C., O’Connor, K., … & Evers, B. M. (2012). Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer research, 72(6), 1504-1517.

[15] Lim, T. K. (Ed.). (2012). Edible medicinal and non-medicinal plants: Volume 3, fruits (Vol. 3). New York: Springer Science & Business Media.

[16] Chadalapaka, G., Jutooru, I., Chintharlapalli, S., Papineni, S., Smith III, R., Li, X., & Safe, S. (2008). CURCUMIN decreases the expression of NF-κB–regulated antiapoptotic and proliferative proteins in experimental lung cancer. AACR.

[17] Jutooru, I., Chadalapaka, G., Lei, P., & Safe, S. (2010). Inhibition of NFκB and pancreatic cancer cell and tumor growth by curcumin is dependent on specificity protein down-regulation. Journal of Biological Chemistry, 285(33), 25332-25344.

[18] Li, J., Cao, B., Liu, X., Fu, X., Xiong, Z., Chen, L., … & Peng, S. (2018). Hydroxycitric acid suppresses intestinal adenoma and adenocarcinoma in ApcMin/+ mice by inhibiting inflammation and cellular proliferation. Environmental toxicology and pharmacology, 57, 41-49.

[19] Chen, J., Wang, L., Li, L., Lu, Y., & Bai, M. (2017). Hydroxycitric acid suppresses apoptosis in lipopolysaccharide-induced RAW264. 7 macrophage cells through inhibition of the ROS-mediated activation of the p38 MAPK pathway. Molecular medicine reports, 15(1), 437-443.

[20] Roy, S., Metya, S. K., Sannigrahi, S., Rahaman, N., & Ahmed, F. (2015). Treatment with Garcinia cambogia extract ameliorates visceral adiposity and improves glucose tolerance in high-fructose fed rats. Journal of complementary & integrative medicine, 12(2), 117-125.

[21] Jena, B. S., Jayaprakasha, G. K., Singh, R. P., & Sakariah, K. K. (2002). Chemistry and biochemistry of (-)-hydroxycitric acid from Garcinia. Journal of agricultural and food chemistry, 50(1), 10-22.

[22] Bai, X., Zhang, Y., Zhao, S., Wang, Z., Zhang, X., Wang, C., … & Tian, G. (2016). Effects of oral gavage treatment with β-glucan and Garcinia cambogia extract on syngeneic colorectal cancer in C57BL/6 mice. BioMed research international, 2016.

[23] Dhar, P., Bhattacharyya, S., Bhattacharjee, P., Ghosh, A., Sarkar, M., Ghosh, S., & Mukherjee, S. (2015). Tumor inhibitory activity of garcinol against human breast adenocarcinoma cells. Molecular and cellular biochemistry, 405(1), 241-253.

[24] Dhar, P., Senapati, S., Biswas, S., Das, S., Ray, M., Sarkar, M., … & Mukherjee, S. (2019). Phase I safety and pharmacokinetic study of garcinol in cancer patients. Cancer Chemotherapy and Pharmacology, 83(5), 921-930.

[25] Kumar, G., Banu, G. S., Murugesan, A. G., Rajasekara Pandian, M., Kavimani, S., Babu, A. V., & Yang, B. (2017). Garcia extract enhances the antitumor efficacy of gemcitabine in pancreatic cancer. Frontiers in pharmacology, 8, 280.

[26] Shay, K. P., Moreau, R. F., Smith, E. J., Smith, A. R., & Hagen, T. M. (2009). Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential. Biochimica et Biophysica Acta (BBA)-General Subjects, 1790(10), 1149-1160.

[27] Porporato, P. E., Payen, V. L., Pérez-Escuredo, J., De Saedeleer, C. J., Danhier, P., Copetti, T., … & Sonveaux, P. (2014). A mitochondrial switch promotes tumor metastasis. Cell reports, 8(3), 754-766.

[28] Feuerecker, B., Pirsig, S., Seidl, C., Aichler, M., Feuchtinger, A., Bruchelt, G., & Senekowitsch-Schmidtke, R. (2012). Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo. Cancer biology & therapy, 13(14), 1425-1435.

[29] Shi, D., Liu, H., Stern, J. S., Yu, P., & Liu, S. (2009). Alpha-lipoic acid induces apoptosis in hepatoma cells via the PTEN/Akt pathway. FEBS letters, 583(22), 3693-3699.

[30] Zhang, G., Wang, Y., Zhang, Y., Wan, X., Li, J., Liu, K., … & Wang, F. (2012). Anti-cancer activities of tea epigallocatechin-3-gallate in breast cancer patients under radiotherapy. Current molecular medicine, 12(2), 163-176.

[31] Wang, Y., Huang, S., Sahin-Tóth, M., & Lawrence, M. C. (2007). Modulation of electron transfer reactivity of the human alpha-lipoic acid redox pair by protonation and Li+ coordination. Molecular and Cellular Biochemistry, 305(1), 71-82.

[32] Dong, L. F., Jameson, V. J. A., Cerny, J., Lin, J. H., Komer, L., Whitehead, R., … & Koumenis, C. (2011). Mitochondrial targeting of vitamin E succinate enhances its pro-apoptotic and anti-cancer activity via mitochondrial complex II. The Journal of biological chemistry, 286(5), 3717-3728.

[33] Na, M. H., Seo, E. Y., Kim, W. K., & Sung, M. K. (2013). Effects of α-lipoic acid on cell proliferation and apoptosis in MDA-MB-231 human breast cells. Nutrition research and practice, 7(5), 365-371.

[34] Andreadi, C. K., Howells, L. M., Atherfold, P. A., & Manson, M. M. (2006). Involvement of Nrf2, p38, B-Raf, and nuclear factor-kappa B, but not phosphatidylinositol 3-kinase, in induction of hemeoxygenase-1 by dietary polyphenols. Molecular pharmacology, 69(3), 1033-1040.

[35] Zhao, Y., Joshi-Barve, S., Barve, S., & Chen, L. H. (2004). Eicosapentaenoic acid prevents LPS-induced TNF-α expression by preventing NF-κB activation. Journal of the American College of Nutrition, 23(1), 71-78.

[36] Kim, B. H., Sung, E. J., Jun, N. R., Yu, S. S., Yoon, Y. J., Kim, J. M., & Kim, M. (2015). α-Lipoic acid attenuates LPS-induced IL-6 production in adipocytes through PI3K-mediated inhibition of the NF-κB pathway. PloS one, 10(12), e0145320.

[37] Sayin, V. I., Ibrahim, M. X., Larsson, E., Nilsson, J. A., Lindahl, P., & Bergo, M. O. (2014). Antioxidants accelerate lung cancer progression in mice. Science translational medicine, 6(221), 221ra15-221ra15.

[38] Natsvlishvili, N., Gogichaishvili, N., Gelenidze, M., Donadze, N., & Kavtaradze, G. (2015). Molecular mechanisms underlying anticancer effects of alpha lipoic acid. Drug metabolism reviews, 47(3), 351-358.

[39] Nie, D., Krishnamoorthy, S., Jin, R., Tang, K., Chen, Y., Qiao, Y., … & Yu, D. (2011). Mechanisms regulating tumor angiogenesis by 12-lipoxygenase in prostate cancer cells. Journal of Biological Chemistry, 286(41), 35801-35811.

[40] Ying, W., Garnier, P., & Swanson, R. A. (2003). NAD+ repletion prevents PARP-1-induced glycolytic blockade and cell death in cultured mouse astrocytes. Biochemical and biophysical research communications, 308(4), 809-813.

[41] Carroll, R. E., Benya, R. V., Turgeon, D. K., Vareed, S., Neuman, M., Rodriguez, L., … & Brendel, K. (2000). Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer prevention research, 4(3), 354-364.

[42] Gonçalves, C., Dinis, T., & Batista, M. T. (2005). Antioxidant properties of proanthocyanidins of Uncaria tomentosa bark decoction: a mechanism for anti-inflammatory activity. Phytochemistry, 66(1), 89-98.

[43] Lesser, G. J., Case, D., Stark, N., Williford, J., Giguere, J., Garino, A., … & Mao, J. J. (2013). A randomized, double-blind, placebo-controlled study of oral alpha-lipoic acid to improve depression associated with hepatitis C interferon therapy. Digestive diseases and sciences, 58(3), 700-708.

[44] Angstwurm, M. W., Engelmann, L., Zimmermann, T., Lehmann, C., Spessert, R., Abel, P., … & Strauss, D. C. (2007). Selenium in Intensive Care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock. Critical care medicine, 35(1), 118-126.

[45] Hardie, D. G. (2012). Organismal carbohydrate and lipid homeostasis. Cold Spring Harbor perspectives in biology, 4(5), a006031.

[46] Jose, C., Hébert-Chatelain, E., Bellance, N., Larendra, A., Su, M., Nouette-Gaulain, K., & Rossignol, R. (2011). Revisiting the mitochondrial pyruvate carrier: current knowledge and therapeutic prospects for cancer. Mitochondrion, 11(5), 727-734.

[47] Trachootham, D., Zhou, Y., Zhang, H., Demizu, Y., Chen, Z., Pelicano, H., … & Huang, P. (2006). Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by β-phenylethyl isothiocyanate. Cancer cell, 10(3), 241-252.

[48] Smith, A. R., Shenvi, S. V., Widlansky, M., Suh, J. H., & Hagen, T. M. (2004). Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Current medicinal chemistry, 11(9), 1135-1146.

[49] Fulda, S., Galluzzi, L., & Kroemer, G. (2010). Targeting mitochondria for cancer therapy. Nature reviews Drug discovery, 9(6), 447-464.

[50] González-Sarrías, A., Núñez-Sánchez, M. A., Tomé-Carneiro, J., Tomás-Barberán, F. A., García-Conesa, M. T., & Espín, J. C. (2017). Comprehensive characterization of the effects of ellagic acid and urolithins on colorectal cancer and key-associated molecular hallmarks: MicroRNA cell specific induction of CDKN1A (p21) as a common mechanism involved. Molecular nutrition & food research, 61(11), 1700221.

[51] Jiang, X., Zhang, Y., Li, Z., & Chan, C. Y. (2010). α-lipoic acid inhibits vomitoxin-induced cell cytotoxicity and apoptosis via preservation of mitochondrial function in RAW264. 7 macrophages. Food and chemical toxicology, 48(7), 1760-1767.

[52] Karpagam, K., Raj, K. J. A., Varalakshmi, B., & Packiavathy, A. S. C. V. (2016). Anticancer efficacy of α lipoic acid on human breast cancer MCF-7 cells. Journal of pharmacy research, 10(2), 119-124.

[53] Ying, H., Kang, Y., Zhang, H., Zhao, H., Zhang, X., Chen, J., … & Jin, H. (1993). Relationships between the structures and biological activities of recombinant human tumor necrosis factor, lymphotoxin and their analogs. Biochemical and biophysical research communications, 197(2), 672-679.

[54] Wenzel, U., Nickel, A., & Daniel, H. (2005). α-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2−·-generation. Apoptosis, 10(2), 359-368.

[55] Shara, M., Ohia, S. E., Yasmin, T., Zardetto‐Smith, A., Kincaid, A., Bagchi, M., … & Stohs, S. J. (2005). Dose‐and time‐dependent effects of alpha‐lipoic acid on gene expression in skeletal muscle cells. Molecular Nutrition & Food Research, 49(11), 1085-1094.

[56] Cremer, D. R., Rabeler, R., Roberts, A., & Lynch, B. (2006). Safety evaluation of α-lipoic acid (ALA). Food and Chemical Toxicology, 44(8), 1225-1229.

[57] Filipčík, P., Rentinò, C., Novotná, M., & Škrabáková, E. (2006). Molecular aspects of lipoic acid in the prevention of diabetes complications. General physiology and biophysics, 25(4), 319-326.

[58] Mijnhout, G. S., Kollen, B. J., Alkhalaf, A., Kleefstra, N., & Bilo, H. J. (2012). Alpha lipoic acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials. International journal of endocrinology, 2012.

[59] Wang, Z., Gleichmann, H., & Thomson, A. H. (2008). Development and validation of a high performance liquid chromatography–mass spectrometry method for simultaneous quantification of sodium-dependent vitamin C transporter SVCT2 substrates in human plasma. Journal of chromatography B, 864(1-2), 150-157.

[60] Teichert, J., Preiss, R., Lutjohann, D., Oette, K., Haughey, N., & Stein, J. (2007). Pharmacokinetics of α-lipoic acid in subjects with severe kidney damage and end-stage renal disease. Journal of clinical pharmacology, 47(11), 1419-1427.