I knew someone who recently passed away from Glioblastoma Multiforme, a fast-growing and aggressive brain tumor. I suggested some things to his wife, but she chose to believe their doctor's prognosis that her husband would live another five years. However, I urged her to do some research because typically this type of cancer has a one-year survival rate after diagnosis. They didn't ask me any questions about it and unfortunately, her husband passed away about a year later.
It's important to note that this cancer is very aggressive and typically has a poor one-year survival rate.
While the two below supplements cannot cure the cancer, studies have shown that they can potentially increase survival time. One of the supplements was even shown to do so in a human study with just 20 mg/day.
The first supplement I would like to discuss is Melatonin. Melatonin has the ability to cross the blood-brain barrier (BBB) which is useful and needed in this case.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001209/#:~:text=One important characteristic of melatonin, than exist in the blood.
A relevant quote from the above link confirms that melatonin crosses the BBB:
One important characteristic of melatonin is its permeability into the brain. It readily passes through the blood-brain-barrier and accumulates in the central nervous system at substantially higher levels than exist in the blood.
Melatonin also has anticancer effects as discussed in this next link :
Here is a very relevant quote from the above link describing some of the anticancer effects of melatonin:
Moreover, the evidence is compelling that melatonin has a variety of anti-cancer effects, such as its inhibition of cancer cell viability, proliferation, progression, and metastasis or even inhibition of cancer initiation [3,4].
Melatonin is also useful for use in people with GBM and also has synergy with temozolomide ( an antineoplastic used for GBM treatment) as discussed here:
Glioblastoma is the most prevalent primary tumor of brain. Furthermore, glioblastoma is a highly aggressive and lethal type of cancer; the average of life expectancy is reported to be less than 1 year after it is diagnosed. Because of the difficulty with complete surgical resection and high resistance of glioblastoma to existing chemotherapy agents, treatment of these patients remains exceedingly complicated. Therefore, there is an urgent need for developing unconventional therapeutic strategies in the treatment of patients with malignant glioblastoma. In the past few years, different investigations have shown the existence of stem cell-like cells in solid tumors involving malignant glioblastomas . Stem cell-like cells are important built-in multidrug-resistant and pluripotent cells that commonly develop drug resistance and continue to proliferative after a chemotherapy regimen. Accordingly, the therapeutic approaches that cannot eradicate the brain tumor stem cells (BTSCs) are expected to be unsuccessful. While these treatments may be successful for killing an appreciable number of tumor cells and causing a transitory regression, they fail to alter cancer relapse . For the purpose of achieving a persistent long-lasting treatment of glioblastoma patients, it is a requirement to discover and develop novel therapeutic strategies for targeting both BTSCs and tumor bulk.
Martin and colleagues  investigated the properties of melatonin and its combination with chemotherapeutic agents on these multi-drug resistant brain tumor stem cells. Results showed that melatonin and chemotherapeutic drugs in combination induced a remarkable synergistic toxicity against BTSCs and malignant A172 glioma cells. Co-treatment with temozolomide as current agent for remission of malignant glioma with melatonin, significantly correlated with down-regulated expression of ABCG2/BCRP and subsequent inhibition of ABC transporter functions. In fact, melatonin significantly elevated DNA methylation of the promoter of ABCG2/BCRP; thus, the expression properties and function of ABCG2/BCRP were prohibited due to the preincubation melatonin with a DNA methyltransferase inhibitor (DNMTi). Hence, their findings highlight a potent association between the decrease of ABCG2/BCRP activities and the synergistic toxicity of melatonin and therapeutic agents. By inducing DNA methylation in proto-oncogenes, melatonin also could be considered as a promising chemical for defeating multi-drug resistance in malignant glioblastomas, and improving the effectiveness of current chemotherapeutic regimens.
Melatonin also synergizes with other drugs used to fight GBM as discussed here:
Here is a relevant quote :
Data presented here showed that combination of melatonin with chemotherapeutics has a synergistic toxic effect both in BTSC and glioblastoma cell lines. Thus, melatonin increases toxicity of several drugs including temozolomide, current treatment for malignant glioblastoma.
The fact that melatonin can increase the toxicity toward GBM may allow for lower dosing of these chemotherapeutics in some cases where that would be desirable for certain patients who are reacting negatively to the anticancer medication.
Melatonin can also help reduce the damage caused to the body by these chemotherapeutic and radiotherapy agents, which would be very useful in reducing unwanted chemo side effects as well as fight multidrug resistance, inhibit stem like cell proliferation in GBM and decrease the viability and inhibit the proliferation of glioblastoma cells as discussed here in this 2021 review:
Here is a relevant quote from the review:
Glioma stem-like cells are subpopulation in glioblastoma, they play a crucial role in the tumor growth maintenance and recurrence [152,153,154], and promote self-renewing capacity and tumor propagation [155,156,157]. Melatonin showed an anticancer effect against glioblastoma, and it was also reported to overcome the multi-drug resistance in glioblastoma treatment [158,159,160]. Sung et al. recently have investigated the impact of combination of melatonin with vorinostat on the expression of transcription factor EB and apoptosis in glioblastoma cells and glioma cancer stem cells. The expression of transcription factor EB, which needs oligomerization to regulate transcription, was reported to be increased in glioblastoma. The combination of vorinostat and melatonin induce a downregulation of the transcription factor EB and oligomerization, which increased apoptosis related gens, hence, cells apoptosis was activated . In another study, Chen et al. have studied the roles of melatonin and the associated mechanisms against glioblastoma stem-like cells. Their results demonstrated that melatonin altered the glioblastoma stem-like cells biology and inhibited glioblastoma stem-like cells proliferation. Moreover, melatonin showed to alter the transcription factors profile inhibiting the initiation and propagation of tumor. In addition to the impairment of EZH2–STAT3 interaction and EZH2 S21 phosphorylation, melatonin has multiple roles in attenuating several key signals related to survival and self-renewal in glioblastoma stem-like cells . Lai et al. have studied the microenvironment of glioma investigating the correlation of melatonin treatment and molecular markers in glioblastoma multiform including SIRT1, CCL2, ICAM-1, and VCAM-1. Their results showed melatonin administration increased the expression of SIRT1, which inhibit the growth and proliferation of glioma cells . In another recent study, Fernandez-Gil et al. have explored whether treatment with melatonin can restore the oxidative phosphorylation after metabolic switch to glycolysis in glioblastoma cells. The results showed that melatonin significantly decreased the viability and inhibited the proliferation of glioblastoma cells. Besides, it modulates a metabolic shift from glycolysis to oxidative phosphorylation, which lead to a reduction in the malignant properties of glioblastoma cells . Additionally, it was reported that the melatonin antitumor effect can be through suppression of the EZH2-NOTCH1 signaling axis in glioblastoma stem-like cells . Moreover, several studies have shown the melatonin impact on glioblastoma cells via enhancing apoptosis and inhibiting cell migration and invasion [165,166,167].
Lastly regarding melatonin, in one small study, it increased the survival time of glioblastoma patients as discussed here:
Here is a relevant quote from the study:
At present, no chemotherapy has appeared to influence its prognosis. On the other hand, recent advances in brain tumor biology have suggested that brain tumor growth is at least in part under a neuroendocrine control, mainly realized by opioid peptides and pineal substances. On this basis, we evaluated the influence of a concomitant administration of the pineal hormone melatonin (MLT) in patients with glioblastoma treated with radical or adjuvant radiotherapy (RT). The study included 30 patients with glioblastoma, who were randomized to receive RT alone (60 Gy) or RT plus MLT (20 mg/daily orally) until disease progression. Both the survival curve and the percent of survival at 1 year were significantly higher in patients treated with RT plus MLT than in those receiving RT alone (6/14 vs. 1/16). Moreover, RT or steroid therapy-related toxicities were lower in patients concomitantly treated with MLT. This preliminary study suggests that a radioneuroendocrine approach with RT plus the pineal hormone MLT may prolong the survival time and improve the quality of life of patients affected by glioblastoma.
The study mentioned above was conducted in 1996, which is 27 years ago. Surprisingly, there have been no follow-up studies on Glioblastoma Multiforme patients using higher doses of melatonin, despite the clear benefits observed in the study even with just 20 mg/day. This raises the question of why further studies using higher doses of melatonin were not conducted, especially considering its excellent safety profile that surpasses other treatments used for GBM. Additionally, melatonin is affordable and easily accessible. It's unclear if this is simply an unintentional oversight or if there are other factors at play.
To help you understand the potential benefits of higher doses of melatonin, a study conducted on Parkinson's disease patients administered 50 mg of melatonin per day. The results showed that this dose was able to reduce levels of oxidative stress, which is a significant contributor to disease progression, to similar levels found in healthy individuals.
A relevant study quote :
At baseline, plasma levels of lipoperoxides, nitric oxide metabolites, and carbonyl groups in proteins were significantly higher in PD patients than in the healthy control group (Figures 1(a)–1(c), respectively). Conversely, the plasma activity of catalase was lower in the healthy control group than in PD patients (Figure 1(d)). These data suggest the existence of an active, persistent oxidative stress in PD. After three months of treatment with melatonin, the levels of lipoperoxides, nitric oxide metabolites, and carbonyl groups in proteins were lower than in the placebo group and were statistically similar to the levels of healthy controls. The activity of catalase was increased with the treatment with melatonin at levels similar to the control group.
To treat ALS patients, melatonin was administered at a dosage of 300 mg per day for up to two years in the form of suppositories. This is noteworthy because melatonin has poor bioavailability, estimated to be between 3% to 15%. Suppository delivery is believed to have significantly higher bioavailability, making it a more effective method of administering melatonin.
Here is a relevant study quote:
' We found that melatonin attenuates glutamate-induced cell death of cultured motoneurons. In SOD1G93A-transgenic mice, high-dose oral melatonin delayed disease progression and extended survival. In a clinical safety study, chronic high-dose (300 mg/day) rectal melatonin was well tolerated during an observation period of up to 2 yr. Importantly, circulating serum protein carbonyls, which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were normalized to control values by melatonin treatment. This combination of preclinical effectiveness and proven safety in humans suggests that high-dose melatonin is suitable for clinical trials aimed at neuroprotection through antioxidation in ALS. '
The ALS study mentioned earlier, conducted in 2006, showed the safety of using 300 mg/day of melatonin for up to 2 years.
Finally, it is worth noting that Dr. Shallenberger has reported using 360 mg/day in stage 4 cancer patients in this video: https://youtu.be/Roh4lQXneQg
Moving on to the next supplement, I'd like to discuss Berberine. Like melatonin, Berberine is able to cross the blood-brain barrier and has a good safety profile that surpasses currently available treatments for Glioblastoma Multiforme. While there is less information available about the relationship between Berberine and cancer compared to melatonin, recent studies have demonstrated that Berberine has multiple anti-cancer effects. Moreover, Berberine has been shown to work synergistically with certain chemotherapeutic agents, as discussed here:
Here is a relevant quote :
Results: MTT assay results showed berberine inhibited cell proliferation of human breast cancer cell lines MCF-7 and MDA-MB-231 in a dose-dependent manner. Co-treatment with berberine and cisplatin or 5-Fu significantly inhibited cell viability of MCF-7 cells than that with berberine or chemotherapeutic drugs alone. Western blotting results demonstrated that the level of cleaved caspase-3 obviously increased in MCF-7 cells treated with berberine in combination with cisplatin than the monotherapy alone. Moreover, the ratio of Bax/Bcl-2 was upregulated in the group of combination therapy with berberine and cisplatin than that with monotherapy alone. Transwell assay data showed that berberine in combination with cisplatin significantly decreased cell migratory ability of MCF-7 cells. Conclusion: Berberine showed synergistic effects in combination with chemotherapeutic drugs to remarkably inhibit cell proliferation and suppress cell migration of breast cancer cells.
This next review discusses some of the anticancer effects of berberine:
Here is a relevant quote :
'The traditional Chinese medicine BBR has been shown to affect cell cycle, cell apoptosis, cell autophagy, and the tumor microenvironment. BBR has also been shown to exert anti-inflammatory and antioxidant effects. Tumor immunotherapy is a hotspot for tumor therapy in recent years, immune-suppressants such as PD-1/PD-L1 suppressants have emerged one after another. However, it is difficult to be widely used in clinic due to their high prices. BBR as an effective immunomodulator and a kind of cheap Chinese traditional drug, is expected to be widely used in clinical practice as an ideal drug for immunotherapy.
As studies showed, BBR exerted its role on autophagy through different mechanisms. In several cancer cells, BBR inhibited cell proliferation by inducing autophagy and also reversed drug resistance by regulating cell autophagy.45,46 However, in mature adipocytes, BBR maintained the cellular homeostasis by inhibiting autophagy.47 Studies showed that autophagy plays an important role in maintaining a stable intracellular environment.92,93 We inferred that autophagy plays different roles in cells. On the one hand, tumor cells evaded apoptosis through decreasing autophagy level; therefore, BBR treatment up-regulated autophagy and led to cancer cell death. On the other hand, BBR treatment lowered the original high level of autophagy in mature adipocytes to contribute to maintenance of a stable intracellular environment. Regulation of BBR on autophagy is complicated; therefore, studies are needed to make further progress on regulation of BBR on autophagy.
I know, anticancer effects definitely, but what about glioblastoma? To that point, this 2015 study points out one of the ways that berberine may be effective against glioblastoma :
Here is an important quote from the link :
Our results showed that berberine possesses a potent antitumor effect against some glioblastoma cells. It can effectively induce glioblastoma cells to undergo cellular senescence. Interestingly, while berberine has been reported to exert its cytotoxic effect by inducing apoptosis in numerous types of cancer cells (13,16,18,19), none of the glioblastoma cell lines we tested in this study showed signs of increased apoptosis in response to berberine treatment. Therefore, induction of cellular senescence (loss of a cell's power of division and growth) is probably the major mechanism by which berberine exerts its antitumor effect against glioblastoma cells. Indeed, induction of senescence has recently been recognized to be an important therapeutic strategy for various types of cancer (25,26). We further showed that the level of EGFR was greatly reduced in berberine-treated cells and that pharmacologic inhibition or RNA interference of EGFR similarly induced cellular senescence of glioblastoma cells. Accompanying the downregulation of EGFR, the RAF-MEK–ERK signaling pathway downstream of EGFR was remarkably inhibited in berberine-treated cells. Because the cellular senescence induced by berberine could be rescued by introduction of constitutive active MKK, we conclude that the induction of cellular senescence in berberine-treated glioblastoma cells is likely mediated by the downregulation of the EGFR–RAF–MEK–ERK pathway. Because EGFR amplification is characteristic of classic subtype of glioblastoma multiforme (GBM) and sustains the proliferation of GBM (27–29), the effective downregulation of EGFR by berberine suggests that use of berberine could be considered in the treatment of GBM.
To further delve into berberine and glioblastoma, this 2022 abstract looks at various methods of action of berberine that work against glioblastoma and reaches the conclusion that berberine is a good choice for glioblastoma multiforme :
Here is a relevant quote :
The most typical malignant brain tumor, glioblastoma multiforme (GBM), seems to have a grim outcome, despite the intensive multi-modality interventions. Literature suggests that biologically active phytomolecules may exert anticancer properties by regulating several signaling pathways. Berberine, an isoquinoline alkaloid, has various pharmacological applications to combat severe diseases like cancer. Mechanistically, it inhibits cell proliferation and invasion, suppresses tumor angiogenesis, and induces cell apoptosis. The antitumoral effect of berberine in GBM is increasingly recognized. This review sheds new light on the regulatory signaling mechanisms of berberine in various cancers, proposing its potential role as a therapeutic agent for GBM.
Unfortunately, the full study for the above link is behind a paywall.
Lastly, this final berberine/glioblastoma study goes even deeper into the methods of action of berberine against glioblastoma :
Here is a relevant quote from the study :
Berberine significantly inhibited the proliferation of human glioma U-87 cells, and induced apoptosis in the U-87 and LN229 cells by downregulating Bcl-2, and upregulating Bax and caspase-3. In addition, berberine also inhibited migration and invasion of the glioma cells. Furthermore, berberine exerted its effects on the proliferation, migration, invasion, and apoptosis of glioma cells by inhibiting the TGF-β1/SMAD2/3 signaling pathway, and exogenous TGF-β abrogated the pro-apoptotic and anti-oncogenic effects of berberine.
Berberine inhibits glioma progression by targeting the TGF-β1/SMAD2/3 signaling pathway.
In summary, both Melatonin and Berberine have excellent safety profiles and can be discussed with your doctor or oncologist. I have already mentioned the dosing of Melatonin previously.
Regarding Berberine, human studies have shown that a dosage of 1500 mg per day, divided into three doses of 500 mg each (taken after breakfast, lunch, and dinner), has demonstrated efficacy and safety in individuals with diabetes, as discussed here:
Here is a relevant quote from the study of berberine in people with type two diabetes:
In study A, 36 adults with newly diagnosed type 2 diabetes were randomly assigned to treatment with berberine or metformin (0.5 g t.i.d.) in a 3-month trial. The hypoglycemic effect of berberine was similar to that of metformin. Significant decreases in hemoglobin A1c (HbA1c; from 9.5% ± 0.5% to 7.5% ± 0.4%, P<0.01), fasting blood glucose (FBG; from 10.6 ± 0.9 mmol/L to 6.9 ± 0.5 mmol/L, P<0.01), postprandial blood glucose (PBG; from 19.8 ± 1.7 to 11.1 ± 0.9 mmol/L, P<0.01) and plasma triglycerides (from 1.13 ± 0.13 mmol/L to 0.89 ± 0.03 mmol/L, P<0.05) were observed in the berberine group. In study B, 48 adults with poorly controlled type 2 diabetes were treated supplemented with berberine in a 3-month trial. Berberine acted by lowering FBG and PBG from one week to the end of the trial. HbA1c decreased from 8.1% ± 0.2% to 7.3% ± 0.3% (P<0.001). Fasting plasma insulin and HOMA-IR were reduced by 28.1% and 44.7% (P<0.001), respectively. Total cholesterol and low-density lipoprotein cholesterol (LDL-C) were decreased significantly as well.
It's worth noting that one of the most commonly reported side effects of Berberine in the study mentioned above was a gastrointestinal disturbance. Taking Berberine after a meal may help prevent gastrointestinal upset.
Finally, this study shows that Berberine and Melatonin have synergy together in fighting lung cancer cells:
Here are some relevant quotes from the study :
Treatment with melatonin effectively increased the berberine-mediated inhibitions of cell proliferation, colony formation and cell migration, thereby enhancing the sensitivities of lung cancer cells to berberine. Melatonin also markedly increased apoptosis induced by berberine. Further mechanism study showed that melatonin promoted the cleavage of caspse-9 and PARP, enhanced the inhibition of Bcl2, and triggered the releasing of cytochrome C (Cyto C), thereby increasing the berberine-induced apoptosis. Melatonin also enhanced the berberine-mediated inhibition of telomerase reverses transcriptase (hTERT) by down-regulating the expression of AP-2β and its binding on hTERT promoter. Moreover, melatonin enhanced the berberine-mediated inhibition of cyclooxygenase 2 (COX-2) by inhibiting the nuclear translocation of NF-κB and its binding on COX-2 promoter. Melatonin also increased the berberine-mediated inhibition of the phosphorylated Akt and ERK. Collectively, our results demonstrated that melatonin enhanced the antitumor activity of berberine by activating caspase/Cyto C and inhibiting AP-2β/hTERT, NF-κB/COX-2 and Akt/ERK signaling pathways.
In summary, melatonin sensitized NSCLC cells to berberine and enhanced the growth inhibitory effect of berberine by simultaneously targeting caspase/cytochrome C, AP-2β/hTERT, NF-kB/COX-2, Akt/ERK signaling pathways. These findings provide new insights into understanding the molecular mechanisms by which melatonin sensitizes NSCLC cells to berberine treatment, and suggest some clues for the development of new therapeutic strategies in human lung cancer therapy.
In conclusion, Melatonin and Berberine are two supplements that are worth discussing with your doctor or oncologist to determine if they could be helpful for you or your loved one. It's important to ensure that these supplements are safe to take alongside any other medications or treatments that are being administered.