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.
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