Thursday, 29 November 2018

Acetazolamide - a new drug for a cocktail approach?

Acetazolamide came into medical use in 1952. Acetazolamide, sold under the trade name Diamox among others, is a medication used to treat glaucoma, epilepsy, altitude sickness, periodic paralysis... There has been a lot of research on Acetazolamide on invitro glioblastoma cells.

In July 2018, an interesting study was published about the use of Acetazolamide in mice. Unfortunately, I missed it and now I decided to write about it.

The study showed that repurposing ACZ might be particularly effective in a subgroup of MGMT promoter methylated tumors that have high BCL-3 expression.

ACZ greatly increased the effectiveness of temozolomide in some types of glioblastoma cells. The effectiveness of ACZ depended on its administration schedule. In experiments with mice, a dose of 5 mg / kg ACZ was used, which seems to be achievable in humans.

The most impressive results were in mice with glioblastoma GBM43S (BCL-3 high):

Kaplan-Meier curves of mice bearing intracranial GBM43S PDX (n = 7 per group) treated with TMZ on days 5, 7, and 9 (5 mg/kg
per dose) and/or ACZ on days 5 to 26 (15 mg/kg per day).

Tuesday, 27 November 2018

posted by  oldcookie48

My husband is 77 yr old. He was diagnosed 2013 w/GBM 4. Full Resection & Radiation. Took TMZ for 12 mos, then CCNU for 6 mos. Optune for 15 mos/stopped due to skin issues-skin cancer. Recurrence in 2018. Full resection/radiation. Now on 10th round of TMZ. Taking Ben Wms' Supplement cocktail since 2013. Only RX: Valproic Acid (never had seizures), Celebrex, Bactrim. Only issues are cognitive, motivation, fatigue. He is MGMT meth. Seattle NO says go to 12 mos (that 2 left). UCSF NO suggesting he stop TMZ due to fatigue since no validation it helps past 6 mos. Blood runs are good. 

Stephen, do you think we should finish the last two rds to make 12 or stop at 10?? NO's leaving it up to us. Any other recommendations based on his gene testing below? I have been ill so difficult for me to focus very well. My husband can't focus at all so leaving it up to me. 
Appreciate your thoughts. Thank you kindly. 

Tumor-only sequencing of this recurrent glioblastoma demonstrates a hotspot mutation in the promoter region of the TERT gene, focal deep deletion of the CDKN2A and CDKN2B tumor suppressor genes on chromosome 9p21, focal amplification of the MDM4 oncogene on chromosome 1q32, focal amplification of the PDGFRA oncogene on chromosome 4q12, a nonsense mutation in the PTEN tumor suppressor gene with loss of the remaining wildtype allele, a frameshift mutation in the BCOR tumor suppressor gene, and focal amplification of the EGFR oncogene on chromosome 7p11. This EGFR amplification is accompanied by a missense mutation that localizes within the extracellular ligand-binding domain and has been recurrently found in glioblastomas, often in conjunction with gene amplification as seen in this tumor [refs. 1-2]. This EGFR mutation is present on a majority of the amplified EGFR alleles given its allele frequency of 74%. Extracellular domain mutations in EGFR have been shown to correlate with resistance to type I EGFR inhibitors such as erlotinib but sensitivity to type II EGFR inhibitors [ref. 3]. 

The quantity of somatic mutations and mutational signature of this recurrent tumor is not suggestive of the hypermutation that is known to occur in a subset of gliomas following treatment with alkylating agents such as temozolomide [ref. 4]. 

Chromosomal copy number changes in the tumor include gain of 7 and losses of distal 2p, interstitial 3q, 8p, 9p, 10, portions of 11q, 13q, distal 14q, and distal 
Only 11 of the 1,068 microsatellites assessed in the tumor (<2%) demonstrate instability, consistent with a microsatellite stable tumor. 

Together, the genetic profile is consistent with the diagnosis of recurrent glioblastoma, IDH-wildtype, WHO grade IV. The cytogenetic alterations (trisomy 7, monosomy 10) and genetic alterations (CDKN2A deletion, TERT promoter and PTEN mutations, amplifications of EGFR, PDGFRA, and MDM4) are some of the most common seen in IDH-wildtype glioblastomas arising within the cerebral hemispheres in adults [ref. 1]. Additionally, this glioblastoma demonstrates a truncating mutation in BCOR, which encodes a transcriptional co-repressor protein that is commonly inactivated in pediatric high-grade gliomas but is not known to be a recurrently mutated or deleted gene in adult IDH-wildtype glioblastoma [refs. 5-6]. 
Genetic features of a diffuse lower-grade glioma (e.g. chromosomes 1p/19q co-deletion or mutations involving IDH1, IDH2, TP53, ATRX, CIC, and FUBP1) are not identified.

I’m hoping that someone can help me understand the situation that my husband is currently in. He has right temporal AA3 that was 80% respected in July 2016.  He did Proton radiation. With 6 months of Temozolomide. He also did immunotherapy vaccination at IOZK. He has not been doing any treatment since February of this year when he decided that he didn’t want to use Optune for a little while. His scans have been looking good and his NO said that she felt what remained was “treatment effect.” In June he suffered from a grand mal seizure that we attributed to cutting back on seizure meds. August’s MRI showed what his NO called leaky blood vessels but nothing too serious. November’s MRI was moved up to the end of October because he fell down. It showed a soap bubble  lesion in his cerebellum and brain stem area. A PET scan made her feel confident that it wasn’t tumor recurrence but treatment effect. She didn’t say radiation necrosis even though he is at the two year mark of finishing radiation. She prescribed 4mg of Dex and then had him taper to 2mg. After a week or so of 2mg, his right chin has started to be tingling. She upped his Dex to 8mg but it hasn’t touched his tingling symptom. What I don’t understand is how it took away the balance issues but won’t take away the new symptom of tingling. Are there other potential causes for this symptom that I’m not understanding? How could he have so much inflammation from late effects of radiation when he takes Longvida curcumin, WokVel Boswellia, Celebrex and Dex?? What questions should I be asking her? So far I’m being shut down until they do another MRI, either this Friday or next Wednesday. Any insight would be most appreciated!! Until then I’ll just go scare myself with google.

PS: I’m interested in hyperbaric oxygen therapy if it could help, but am scared it would wake up any more cancer cells.

Thursday, 22 November 2018

Hello Stephen, and all

My aunt's tumour was discovered about a week ago, and she underwent surgery shortly after. The doctor said he was able to remove about 60% of the tumour, which is in her right frontal lobe. She is 65 yrs of age.

Pathology Report:

·         Grade IV Glioblastoma
  • Tumour shows marked cellular pleomorphism, scattered mitosis, and microvascular proliferation.
  • There is no definite tumour necrosis
  • idh(-) wildtype, ATRX(+), GFAP(+), p53(+)
  • The ki67 proliferation status is estimated at 10%
  • Result of MGMT Gene methylation status to follow as an addendum….. still do not have it, but hoping to get this information at the first appt with the oncologist tomorrow morning*
I am trying to get as familiar as I can with GBM and I am doing some research on currently recruiting clinical trials so I can bring them along to the appt with her oncologist tomorrow.

I have discovered 2 trials that she seems to be eligible for (I hope), but I would like to make sure we are strategic in which we decide to choose (does trial phase matter?). I am very new to this topic and was hoping to get some of your thoughts on which might be more beneficial for my aunt based on previous studies etc. I did not see any info in the library about Avelumab (I think it is an immune checkpoint inhibitor) or Marizomib.
Also, in some trials there is the risk of being put in a control group, while it seems in the first trial below, all participants receive the new drug.

1. Avelumab in Patients With Newly Diagnosed Glioblastoma Multiforme (SEJ)

2. A Phase III Trial of With Marizomib in Patients With Newly Diagnosed Glioblastoma

Any other trials or treatment options in Canada that may be worth looking at?

Any input is greatly appreciated,
Thank you,

Monday, 19 November 2018

Phase II Results: TMZ with DISULFIRAM and COPPER (SNO 2018)

The disappointing results of this study are published in the SNO 2018 brochure:


BACKGROUND: Preclinical studies have suggested promising activity for the combination of disulfiram and copper (DSF/Cu) against glioblastoma (GBM) including re-sensitization to temozolomide (TMZ). A previous phase I study demonstrated the safety of combining DSF/Cu with adjuvant TMZ for newly diagnosed GBM. This pilot phase II study aimed to estimate the potential effectiveness of DSF/Cu to re-sensitize recurrent GBM to TMZ. METHOD: This open-label, single-arm phase II study treated recurrent TMZ-refractory GBM patients with TMZ 150mg/m2 on days 1–5 of every 28-day cycle with concurrent daily DSF 80mg TID and Cu 1.5mg TID. Eligible patients must have progressed after standard chemoradiotherapy and within 3 months of the last dose of TMZ. Known IDH-mutant or secondary GBMs were excluded. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall (OS), clinical benefit (stable disease for at least 6  months), and safety. Evaluable patients must have received at least 28 days of DSF/Cu unless stopped due to progression, toxicity, or death.

RESULTS: From March 2017 to January 2018, 23 TMZ-refractory GBM patients were enrolled across seven centers in the United States, and 22 patients were evaluable. The median DSF/Cu duration was 48 days (range: 12–246 days). After a median follow-up of 4.4 months, there were no objective responses, with 6-month PFS of 14% and 6-month OS of 55%. Among 17 patients who had at least 28 days of DSF/Cu, 3 patients (18%) had clinical benefit. Grade 3 toxicities that were possibly related to DFS/Cu included fatigue, headache, anxiety, and elevated alanine transaminase (5% for each).

CONCLUSION: Addition of DSF/Cu to TMZ for TMZ-refractory GBM yielded minimal ORR but demonstrated clinical benefit for a subset of patients. DSF/Cu may have modest TMZ re-sensitization or single-agent activity for recurrent GBM.

Friday, 16 November 2018

Sulbutiamine or / and DCA

DCA is known to be associated with toxicity and neuropathy. For example, in this study (, a dose of 25 mg / kg / day of DCA caused neuropathy in all participants in the study!

Recently this article caught my attention:
High Dose Vitamin B1 Reduces Proliferation in Cancer Cell Lines Analogous to Dichloroacetate
"Inhibition of PDKs by dichloracetate (DCA) exhibits a growth suppressive effect in many cancers. Recently it has been shown that the thiamine co-enzyme, thiamine pyrophosphate reduces PDK mediated phosphorylation of PDH. Therefore, the objective of this study was to determine if high dose thiamine supplementation reduces cell proliferation through a DCA like mechanism.
Results: Thiamine exhibited a lower IC50 value in both cell lines compared to DCA. Both thiamine and DCA reduced the extent of PDH phosphorylation, reduced glucose consumption, lactate production, and mitochondrial membrane potential.
...Although our findings demonstrate that doses of thiamine (mM) required to reduce cancer cell proliferation are similar to DCA, thiamine has few dose limiting toxicities."

According to the authors, the proliferation of cancer cells decreased by 50% at thiamine levels of 4.9 and 5.4 mM. While DCA was required 10.3 and 23.8mM. The question is, is it possible to reach a thiamine level of 4.9-5.4 mM in glioblastoma cells in the brain?

"Thiamine reduces cancer cells proliferation.
The IC50 values for DCA were 23.8 for SK-N-BE and 10.3 mM Panc-1. Comparatively, the IC50 of thiamine was lower than DCA for both cell lines with values of 4.9 for SK-N-BE and 5.4 mM for Panc-1."

The effects of Thiamine on PDH phosphorylation, glucose consumption and lactate production, mitochondrial polarization, ROS production, caspase-3 activity were estimated at 25 mM and therefore are probably not easily achievable.

Sulbutiamine is a synthetic thiamine derivative designed to overcome thiamine’s inherently poor bioavailability. It was designed in the 70’s in Japan in response to widespread thiamine deficiency.

I also found some studies that sulbutiamine penetrates the brain better than benfotiamine and thiamine. It also seems that sulbutiamine is safe in large doses.


"Sulbutiamine shows promising results in reducing fatigue in patients with multiple sclerosis. Sulbutiamine is a lipophilic compound that crosses the blood-brain barrier more readily than thiamine and increases the levels of thiamine and thiamine phosphate esters in the brain."


"...We previously found that sulbutiamine treatment significantly increases thiamine, ThMP, ThDP and ThTP content of rat brain, while the present results show that benfotiamine, at a twice higher dose, is unable to raise the levels of intracerebral thiamine phosphate derivatives.
...Furthermore our results on cultured neuroblastoma cells show that benfotiamine, in contrast to sulbutiamine, does not easily cross cell membranes.
...Our results show that oral administration of benfotiamine leads to significant increases in thiamine, ThMP and ThDP levels in blood, liver but not in the brain. This difference is in agreement with the known pharmacological profile of benfotiamine, i.e. the beneficial effects of the drug concern peripheral tissues but not the central nervous system."

"Sulbutiamine, a highly lipophilic thiamine derivative, is the only antiasthenic compound known to cross the blood-brain barrier and to be selectively active on specific brain structures directly involved in asthenia."

Sulbutiamine is available as a dietary supplement. Unfortunately, there is not enough information about the risk of its effect on tumor growth at low and medium doses and what should be the high dose for an effect similar to DCA.

Saturday, 10 November 2018

Irina’s mom healing cocktail

Dear Stephen, dear all!
I want to apologize in advance for the mistakes, because I have not practiced English for a long time.

Some history:
My mom’s tumor was found on MRI in 2011, doctors did not operate it because it was inconveniently located. One of the best Russian surgery said that we just have to watch it and do MRI each year. Seven years it did not interfere, but gradually grew and changed boundaries, in 2018 epileptic seizures started and appeared contrast on MRI.
07/17/2018 85% of the tumor was removed.
Three courses of TMZ (5/23) and 6 courses of Avastin. After the first course of TMZ and Avastin, MRI showed a reduction in the tumor and a decrease in contrast. Doctors said that radiation therapy should not be done because of the location of the tumor.

Histology results: 
- glioblastoma;
- MGMT methylated;
- no mutation was detected in 599-601 codons of the BRAF gene;
- diffuse expression of GFAP;
- p53 (norm);
- Ki-67 index - 25%;
- expression of synaptophysin;
- IDH1, NF, CD34 (in the tumor endothelium) was not detected in the tumor cells;
- mutations in 4 exogenes of the IDH11 and IDH2 genes were not detected;
- the deletion of the 19q13 locus was not found (the ratio of the number of signals 19q: 19p is 1.34);
- a deletion of the 1p36 locus was detected (the ratio of the number of signals to 1p: 1q is 0.70;
- in the nuclei of tumor cells a tri-, tetrasomy 19 chromosome is detected;
- microsatellite instability by markers NR-21, BAT-25, NR-24, NR-27 was not detected (tumor phenotype with a stable repair system - MSS);
- PD-L1 expression is not determined;
- BRCA1, BRCA2, CHEK2 not found.

My mom's cocktail (weight 63 kg, height 172 cm):
Coriolus versicolor
3150 mg. Better take on empty stomach or with meal?
Nexium (esomeprazole)
60 mg 2 times a day. Two days before chemo, one day after
chemo. Or she should take it constantly?
12 / mg per kilogram 2 times a day and than increasing (ordered but not arrived yet)
Hydroxycitrate (Garcinia cambogia extract) + Lipoic acid + Low Dose Naltrexone (protocol METABLOC)
Hydroxycitrate: 500 mg thrice daily; Sodium R Lipoate: 800 mg twice daily + 5mg before bed time 
ECGC and Sulfofran
Could you please advice on dosage of ECGC? And should she take ECGC and sulfofran only during 5 days of TMZ or all course of TMZ?
Boswellia (wokvel)
Should be taken only during radiation? If my mom doesn't have radiation can boswellia affect the tumor positively, or it just reduce edema and that is all?
What dosage and best trade mark?
Aged Garlic
What dosage?
(Maitake (Grifola frondosa) mycelium - 142 mg)
Is it enough or I better buy Maitake D-fraction?
Perillyl alcohol

I understand that my mom's cocktail is very far from the ideal, but I'm trying to improve it every day.

1. Which mutations do we still need to pass to choose the most effective treatment tactics and select the optimal cocktail? I read on the forum about EGFR, EGFR III and many other mutations, but I have never heard about it from mom’s oncologist.
2. What drugs should I add to my mom’s cocktail that will be maximum effective in her case (Actuante during 23 days off TMZ, disulfiram with copper during 5 days of TMZ, Artemether during 5 days of TMZ, Captopril, Tagamet, Celebrex, Minocycline or other)?
I got a bit confused in such a huge amount of drugs in the Stephen’s library, because in Russia there was absolutely no one to consult on this topic, 3 chemotherapists refused to even listen about such methods.
3. My mom also takes Valproic acid against epilepsy after surgery, but she doesn’t have radiation. Probably we should change it on Keppra, because she is still on TMZ? Or there is no need, because her MGMT is methylated?
4. Are there any drugs - MGMT inhibitors, that can possibly change the status of MGMT methylated to unmethylated?
5. How do you think, should we go from only TMZ to TMZ + lomustine? And make 12 courses (3 TMZ have already done)?
6. Do I understand correctly that I should limit mom’s protein intake to 0.83 grams protein per kilogram body weight?

I want to thank Stephen for the blog! I can’t even express how useful this resource is!
I wish all of you and your loved ones good health!


Friday, 9 November 2018

Questions on Chloroquine for my mom

Hi folks/Stephen,

My mom is a GBM patient who is EGFRvIII amplified, and basis my research and Stephen's inputs, I realised that Chloroquine is a great adjuvant for my mom. I have been reading up on Chloroquine and had the following questions on the same:

1. I am not able to find Chloroquine in my country, but Chloroquine phosphate instead. Can they both be used interchangeably? Is the efficacy of both just as good?

Basis my research, the dosage of Chloroquine should be 150 mg. What should be the dosage of Chloroquine Phosphate, if it can be used interchangeably?

2. I also read that Chloroquine is a chemo sensitiser, but couldn't find any information on what the timing of this drug should be for maximum efficacy.

My mom takes lomustine+temozolomide in the morning. Can you please help me on when the Chloroquine/Chloroquine Phosphate should be timed for maximum efficacy?

3. How long should chloroquine be taken for? Should it just be done till the chemotherapy or should it be done post the chemotherapy too? I see different researches doing this protocol differently.

My mom has completed 3 cycles of temozolomide and 4 cycles of temozolomide+lomustine. We plan to do two more cycles of temozolomide+lomustine and stop the chemo post that.

4. My mom is also doing the supplements in the table below.

a. My major concern is Artemisia since it is an anti malarial drug too. Is it safe to do both? If yes, how I should I time them so that I get the efficacy of both for my mom?

b. Is there any drug reaction that I should be concerned of? I researched on for the interaction list, but all that I could find were two reactions since most of the naturopathic supplements were not there in their database(Interaction list for my mom is here). The two reactions that they talk of is reaction between Chloroquine and Keppra, Chloroquine and Celebrex, how big a concern are they?

SupplementCap count
Boswellia Serratta 500 mg8
Keppra 500 mg2
Curcumin + Piperine 1 g4
Longvida 400 mg2
Metformin 500 mg3
Quercetin 865 mg4
Resveratrol 200 mg2
Bromelain 500 mg6
TMG 1 g3
Reishi 1g2
Mebendezole 100 mg for 3 months + Doxycycline 100 mg for 1 month
(We have skipped the statins from the care oncology protocol fearing it might be too heavy on her liver)
Artimisia 1 g2
Ashwagandha 500 mg1
Selinium 200 mcg1
Vitamin A + D + K2 - 5000 IU1
Molybdenum Glycenate 1g1
Celebrex 200 mg2
Green tea extract 500 mg 40% EGCG2
Marrow Plus6
Echinisea 500 mg3
Astragalus tea 3g1
Juice from 5g of Ginger1
Garlic 2 cloves3

I look forward to your response!

Wednesday, 7 November 2018

Rovalpituzumab Tesirine (DLL3 antibody-drug conjugate) for IDH1-mutant glioma

Cell surface Notch ligand DLL3 is a therapeutic target in isocitrate dehydrogenase mutant glioma

pubmed link

full article download

"DLL3 immunostaining was intense and homogeneous in IDH mutant gliomas, retained in all recurrent tumors, and detected in only 1 of 20 non-tumor brains. Patient-derived IDH mutant glioma tumorspheres overexpressed DLL3 and were potently sensitive to Rova-T in an antigen-dependent manner."

This is particularly interesting because the therapy is currently available in a clinical trial for recurrent GBM and other solid tumors recruiting at multiple locations across the USA.

Saturday, 3 November 2018

CDK4/6 inhibitors

My father was diagnosed with GBM a few months ago and a recent molecular screening suggests that CDK4/6 inhibitors may be of use as a form of therapy due to evidence of 'CDK4 amplification'.  

Following my own research, there seem to be three CDK4/6 inhibitor drugs available:

1) ribociclib (Kisqali) 
2) palbociclib (lbrance) 
3) abemaciclib

Does anyone have any experience with the above drugs in terms of toxicity, side effects, dose etc?

Are there any drugs that are known to, or have some evidence to suggest that they may work synergistically (or to have negative interactions) with these three? 

Apart from the three drugs above, does anyone know of any other CDK4/6 inhibitors?

Any inputs would be much appreciated! Thanks!

Thursday, 1 November 2018

List of Repurposed Drugs

FRom supplementary info of this Article 

Presentation of the main achievements in preclinical studies for GBM, contemplating detailed information such as IC50, IC90, EC50 and LD50 values for repurposed drugs.
Main achievements
New IC50
Chloroquine treatments (10 and 25 μΜ) halved proliferation of primary cultures from GBM specimens and cell lines (U 373 and U 87). Chloroquine inhibited MMP-2 activity and GBM invasion; In an MTT assay, U251, LN229, and U87 glioma cell lines were treated with increasing concentrations of chloroquine for 48 hours (10‑100 μM).
30 μΜ (U251, LN229, U87)
40 μΜ (U251‑TMZR, LN229‑ TMZR, U87‑ TMZR)
Hydroxichloroquine killed glioma cells that were highly resistant to temozolomide, proving its cytotoxicity. Quinoline-based antimalarial compounds are cytotoxic to glioma cells.
Mefloquine effectively killed U251 cells at much lower concentrations than chloroquine. Mefloquine killed U 251 and U 251-TMZ resistant cells in a concentration dependent manner.
10 μΜ (U251, LN229, U87)
15 μΜ (U251‑ TMZR, LN229‑ TMZR, U87‑ TMZR)
Quinoline-based antimalarial compounds are cytotoxic to glioma cells.  In an MTT assay, the U251 and U251-TMZR glioma cell lines were treated with increasing concentrations of quinacrine (10‑100 μΜ) for 48 hours.  In a subcutaneous human xenograft U87 glioma model, nude mice were treated with 50 mg/kg of quinacrine and tumors were harvested after 24 hours. Quinacrine significantly reduced tumor progression.
5 μΜ (U251, LN229, U87)
8 μΜ (U251‑TMZR, LN229‑TMZR, U87‑TMZR)
Pyrvinium pamoate
GBM samples with a CD133 high fraction are much more sensitive to pyrvinium treatment than those with a CD133 low fraction. CD133+ cells decline upon treatment with 200 nmol/L with pyrvinium for 48 hours in both primary (BT428) and recurrent (BT 566) GBM samples. Treated cells with pyrvinium at its IC80 levels for 3 days were intracranially injected in immunodeficient mice, that later displayed no evidence of tumor formation.
239.8 nmol/L (BT241), 122.5 nmol/L (BT486)
Oral administration of mebendazole at 50 mg/kg from day 5 after tumor implantation in C57BL/6 mice slowed tumor growth. 100 mg/Kg daily led to toxicities. 60919 GBM cells were incubated with 0.1 or 1 μM of mebendazole, and 1μM of mebendazole clearly reduced the polymerization of tubulin; this activity of mebendazole was also verified at 0.1 or 0.2 μM after 72 h
0.24 μM (GL261),
1μM (060919 GBM)
Acyclovir at high concentrations (up to 500 mg/mL) inhibited growth in tissue culture of the human glioblastoma cell lines T98G, SNB-19, and U 373 by as much as 68.3%.
In vitro, ritonavir induced a G1-block at the 100-μM dose in GL15 cells. Rats were treated daily with 40 mg/kg, IP, until their death but there was no control over tumor growth, most likely because the therapeutic dose was not reached in the tumor.
50 μmol/L atazanavir induced inhibitory effects in both U 251 and LN229 cells.
Ribavirin treatment (30 μM) leads to a significant decrease in all glioma cell growth. Ribavirin treatment in vivo significantly enhances chemo-radiotherapy efficacy and improves survival of rats and mice orthotopically implanted with gliosarcoma tumors or glioma stem‑like cells, respectively.
53.6 μM (A 172)
27.9 μM (AM-38)
55.0 μM (T98G)
59.7 μM (U87)
664.2 μM (U 138)
257.7 μM (U 251)
76.9 μM (YH-13)
2-80 μM of itraconazole led to cytotoxicity in U87 and C6 cells. Nude mice with U87 subcutaneous tumor xenografts were treated with 75 mg/kg, twice daily, by gavage for 3 weeks. Itraconazole inhibited the proliferation of glioblastoma cells both in vitro and in vivo.
Ciprofloxacin induced tumor cell death in a dose-dependent manner. IC50 reduced to 22.8 μM for ciprofloxacin in the presence of 62.5 μM of temozolomide.

259.3 μM (A 172)
Salinomycin significantly reduced the cell viability of GL261 neurospheres and GL261 adherent cells in a dose-dependent manner. The inhibitory effect was more effective than that of 1-(4-amino-2-methyl-5-pyrimid l)-methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride and vincristine. Salinomycin depleted GL261 neurospheres from tumorspheres and induced cell apoptosis. In addition, it prolonged the median survival time of glioma-bearing mice.
50 μM of minocycline reduced cell viability of U 87, U 251 and C6 glioma cells. Alone, it did not affect cell viability of normal cells (SVGP12 and rat primary astrocytes).
Mice that were injected with C6 cells and treated with minocycline (20 or 100 mg/kg, IP) in saline, daily, during 10 days had a slower tumor growth rate when compared to control group.
30 μM (C6)
Doxycycline exerted mild anti-proliferative effects after high‑concentration treatments (20, 25, 30, and 35 µg/ml) on glioma cell lines U 251HF, U 87 and LN229.
Tigecycline inhibited glioma cell growth in a concentration-dependent way. 10 μM of tigecycline alone did not affect cell viability of normal cells (SVGp12 and rat primary astrocytes).
Tigecycline effectively inhibited tumor growth in the xenograft tumor model of U87 glioma cell, after the administration of tigecycline (100 mg/kg in DMSO), daily, for 10 days.
A significant decrease in cell viability was observed in cells treated for 24h with high concentration of chlorpromazine (≥20 μM). Overall survival significantly improved for U 251-TMZR orthotopic mouse brain tumor models, but not for the U 251 group, after treatment with 5 or 7 mg/Kg, IP for three times a week for 2 weeks and 5 days after tumor implantation.
18.8-27.7 μM (C6)
15 μM (SH-SY5Y)
GBM8401 cells were treated with at concentrations ranging from 5 to 15 μM for 24h. GBM8401 cells were treated concentrations of 10 and 20 μM for 24 h. Thioridazine induces autophagy in GBM8401 and U 87 cells, and has cytotoxic effect at 7.5 μM. U 87 cells were subcutaneously implanted into mice. Thioridazine (5 mg/kg/day, 5 days/week, IP) significantly reduced tumor size. Flow cytometry of propidium iodide-stained glioma cells treated with thioridazine, fluphenazine, or perphenazine (6–50 µM) resulted in a concentration-dependent increase of fragmented DNA up to 94% vs 3% in controls by all agents, with thioridazine being the most potent.
13.7 μM (C6)
11 μM (SH-SY5Y)
Fluphenazine, from 0-24 μM, induced a marked and concentration-dependent decrease in cell viability in glioma C6 cells. Flow cytometry of propidium iodide-stained glioma cells treated with thioridazine, fluphenazine, or perphenazine (6–50 µM) resulted in a concentration-dependent increase of fragmented DNA up to 94% vs 3% in controls by all agents.
19-24.5 μM (C6)
15 μM (SH-SY5Y)
Perphenazine, from 0-24 μM, induced a marked and concentration-dependent decrease in cell viability in glioma C6 cells. Flow cytometry of propidium iodide-stained glioma cells treated with thioridazine, fluphenazine, or perphenazine (6–50 µM) resulted in a concentration-dependent increase of fragmented DNA up to 94% vs 3% in controls by all agents.
15.8 μM (C6)
15 μM (SH-SY5Y)
Treatment with olanzapine (up to 100 μM) inhibits the proliferation of established glioblastoma cell lines and enhances the antiproliferative effect of temozolomide on U 87 and A 172 cells.
27.9 μM (A172)
49.1 μM (U87)
With increasing concentrations, penfluridol significantly suppressed the growth of several glioblastoma cell lines in a concentration and time-dependent manner. Penfluridol (10 mg/kg by oral gavage, daily) led to a 65% suppression of glioblastoma tumor growth (U 87) in mice.
2–5 μM (GBM43, GBM10, GBM44, GBM28, GBM14, T98G, U 251, U 87, SJ‑GBM2, CHLA-200)
Relatively high doses of quetiapine (>25 μM) may inhibit cell proliferation by retarding cell cycle in the G2-M phase. In xenograft tumor model in nude mice, quetiapine (20mg/kg, IP) alone or combined with temozolomide, significantly suppressed tumor growth, displaying a synergistic antitumor effect with TMZ.
Inhibition of migration was dose-dependent, with a near complete blockade at 20 mM lithium for X12 (human biopsy) and U 87 glioma cells. A reduction in viability of about 20% was seen after 48 h of 20 mM lithium treatment in U 87 cells. Lithium concentrations above 5 mM can affect the proliferation, apoptosis and migration of glioma cells via GSK-3 inhibition. Combination with 1.2 mM Lithium potentiated TMZ-induced cell death in TP53wt glioma cells. TMZ combined with Lithium prevented tumor growth in vivo and increased mice median survival times.
Treatment of Hs683 cells with 2.5 μM donepezil for 72 h blocked a large majority of Hs683 cells in division, as also observed for T98G and U373 cells. Mice with orthotopically implanted Hs683 cells and treated with donepezil + TMZ (2 mg/kg + 40 mg/kg, per os, thrice a week, respectively) had a significant increase in survival, while treatment with donepezil alone (2 mg/kg per os, thrice a week) did not show significant benefits.
Memantine (up to 600 μM) had an antiproliferative effect on T98G cells, but not on U 251 cells.
400 μM (T98G)
Paroxetine induced a dose-dependent decrease in cell viability. Concentrations of SSRIs that induced apoptosis are higher than those achieved with the current therapeutic use of these drugs
12–30 μM (C6)
25-50 μM fluoxetine application decreased the viability of various glioma cell lines. The concentrations of SSRIs that induced apoptosis are higher than those achieved with the current therapeutic use of these drugs.
12–30 μM (C6)
Sertraline alone (up to 10 μM) displayed cytotoxicity in U 87 cells. When combined with imatinib or temozolomide, the antiproliferative effect was markedly improved.
3.1-6.8 μM (U 87)
The inhibitory effect of fluvoxamine on actin polymerization was concentration dependent.  20-30 μM was enough to inhibit lamellipodia formation and migration and invasion of U 87 and U 251 cells in vitro. Therapeutic doses of fluvoxamine were sufficient to prevent invasion of GBM cells (A 172, U 87, and U 251). Daily administration of fluvoxamine (50 mg/kg) inhibited GBM cell invasion and prolonged survival in mice bearing GBM tumors.
30 μM
Exposure to imipramine 60 μM for 7 days strongly reduced the ability of U 87 and C6 cells, but not primary cultured rat astrocytes, to form colonies, due to cell death; 10 μM imipramine inhibited mitochondrial activity at a rate dependent on the oxygen content in the atmosphere (from 6% in hypoxia, 11% in average hypoxia, and 19% in hypoxia‑reoxygenation to 26% in 20% oxygen).
10 μM amitriptyline inhibited mitochondrial activity on TG98 cells at a rate dependent on the oxygen content in the atmosphere (from 6% in hypoxia, 11% in average hypoxia, and 19% in hypoxia-reoxygenation to 39% in 20% oxygen). Low-dose amitriptyline (0.14-0.5 mM) has emerged as a potential strategy for inducing inhibition of cellular respiration in tumor cells.
Significant decreases in the proliferation of C6 glioma cells were detected with the increase in the escitalopram concentration and incubation period. Comparing to controls, cell proliferation after 24 h of incubation were 97.7, 85.9, 74.5 and 67.9% for 25, 50, 100 and 200 μM escitalopram, respectively. After 48 h, it was found to be 96.5, 68.0, 50.7 and 39.9% for 25, 50, 100 and 200 μM concentrations, respectively. Results indicate escitalopram induced citotoxitcity and apoptotic events in C6 glioma cells.
106.97 μM (C6)
40, 80, 160, and 360 μg/mL reduced T98G cell numbers to a certain degree relatively to the number of control cells (at 72h); 80, 160, and 360 μg/mL reduced A 172 cell numbers by 20.2%, 23.5%, and 24.8% relatively to the number of control cells.
Valproic acid
5 to 20 mM induced G2/M cell cycle arrest and increased the production of ROS (in U 87, GBM8401, and DBTRG-05MG GBM‑derived cell lines); it inhibited MTT dehydrogenase activity at concentrations over 800 µM (in those 3 GBM cell lines); Epilepsy patients generally accumulate total plasma concentrations in the range of 0.3-0.7 mM, when treated orally with 15-20 mg/kg valproic acid per day (lower concentrations of around 40-200 µM at a daily treatment are observed in the brain indicating valproic acid brain/plasma ratios in the range of 0.07 to 0.28); a dose escalation study in GBM patients defined 60 mg/kg valproic acid per day as maximal tolerable dose which gave rise to median plasma concentrations of about 0.85 mM and a maximal plasma concentration not exceeding 1.4 mM.
1.4 mM (T98G)
1.0 mM (U 251)
1.3 mM (U 87)
5 and 10 μg/ml significantly inhibited the proliferation of U 373 glioma cells at 48 and 72 h.
Classically TMZ resistant cells (SF188 cells) were sensitive to 500 nM, a sufficient concentration to suppress growth in monolayer by approx. 100% over 72 hours; U 251 cells treated with 200 nM were suppressed in growth by 80% and 500 nM doses completely eliminated the cells; IC90 value reported for disulfiram in SF188 cells was 100 nM.
Dimethyl fumarate
It is rapidly metabolized to MMF and has a Cmax in plasma of 15 μM, with an approximate steady state tissue and plasma concentration of 5 μM. GBM cells were treated with MMF (5 μM), enhancing toxicity of velcade and carfilzomib.
Non-cytotoxicity concentration (20 nmol/l) can induce TRAIL‑mediated apoptosis of GSCs; While digitoxin was capable of inhibiting HIF-1α expression in GSC at clinically achievable concentrations (10–25 nM), it required higher concentration than those used for cardiac therapy (2–3 nM);
Increased cell death at a concentration of 10 nM, while 1–5 nM did not reproduce a significant effect.
10− 4 M significantly decreased cell viability of U 87 and microglia; 10 μM reduced the invasion and migration of U 87 spheroid cells after 58h.
There were 26, 51, 58 and 71% cell death induced by 1, 5, 20, and 40 μM lovastatin alone in M059K GBM cells, respectively; A significant increase in cell population at G0/G1 phase was observed when cells were treated with 20 μM lovastatin, indicating that lovastatin was able to arrest the cells at G0/G1 stage.
10 μM was a cytotoxic concentration of simvastatin; 10 μM significantly reduced the number of U 251 and U 87) colonies per field (pro-apoptotic effect); the survival rates (C6 glioma cells) on exposure to 2.5, 5, 10, and 20 μM of simvastatin were 96.17, 53.82, 1.76 and 0.49%, respectively, at 72 h; the survival rates of U 251 cells on exposure to 2.5, 5, 10, and 20 μM of simvastatin were 65.57, 57.59, 25.11 and 21.87%, respectively, at 72 h;
Mevastatin, uvastatin
5 μM was the cytotoxic concentration of mevastatin and fluvastatin; the survival rates of C6 cells on exposure to 1, 2.5, 5, and 10 μM of fluvastatin were 69.70, 54.71, 9.71 and 0.88%, respectively, at 72 h; the survival rates of C6 cells on exposure to 1, 2.5, 5, and 10 μM of mevastatin were 83.82, 58.23, 4.41, and 0.52, respectively, at 72 h; the survival rates of U 251 cells on exposure to 1, 2.5, 5, and 10 μM of mevastatin were 81.44, 58.41, 31.81 and 16.93%, respectively, at 72 h; the survival rates of U 251 cells on exposure to 1, 2.5, 5, and 10 μM of fluvastatin were 63.37, 53.71, 25.45 and 24.08%, respectively, at 72 h.
0.922 μM (A 172)
50 nM induced mild morphological changes in U251 cells; 10 μM stimulated the G1 phase arrest; low concentrations (10 and 50 nM) dose-dependently inhibited the formation of focal adhesion plaques; disorganized phalloidin staining of actin stress fibers was also noted; at concentrations from 10 to 100 nM, cerivastatin drastically reduced FAK phosphorylation at Py397; 1 mg kg−1 cerivastatin per day intraperitoneally significantly delayed subcutaneous U 87 tumor growth (average tumour size decreased by 50.2%).
0.098 μM (A 172)
The IC50 was less than 10 μM in most of U 87 human GBM cells tested (range of 1.260 to 55.63 μM); The ability of pitavastatin to cross the BBB is predicted to be limited as the –log BB was calculated as ‑0.6499; 1 mg kg−1 pitavastatin per day intraperitoneally significantly delayed subcutaneous U 87 tumor growth (tumor size decreased by 74.3%).
0.334 μM (A172 cells)
21.2, 7.30 and 4.80 μM (U87, 2-, 3- and 4-day treatments, respectively)
2.5–5 μmol/L significantly inhibited cell growth and enhanced the inhibition of GSC growth by TMZ; mibefradil (24 mg/kg bodyweight) was administered per oral gavage (GSC-based xenograft mouse model) every 6 hours for 4 days and resulted in significant inhibition of tumor growth.
MMP-2 and MMP-9 activity was reduced to half at captopril concentrations of 30–50 nM, levels easily clinically achieved in humans.
10 mM significantly decreased GBM cell proliferation (U 87, U 251, LN18 and SF767); metformin EC50, as CLIC1 inhibitor, was 2.1 mM, while IAA94 (a well-characterized CLIC1 inhibitor) showed EC50 32 μM (in U 87 cells); metformin time-dependently decreased U 87 cell viability (EC50: 23, 6.6 and 1.7 mM after 24, 48 and 72 hours); metformin dose-dependently reduced CSC viability (EC50: 3.9, 11.3, and 8.0 mM for GBM CSC, after 48 hours of treatment); metformin inhibited CLIC1 conductance in wt GBM CSCs with an EC50 (2.3 mM) similar to U 87 cells; metformin (200-1000 μM) significantly inhibited CSC CLIC1 current during high frequency stimulation (7 days); prolonged treatment (up to 15 days) with low doses of metformin (10‑300 μM) significantly reduced CSC viability.
10 μM inhibited LN229 cell migration (at a much lower concentration compared to its IC50). Repaglinide (1.04 mg/kg) was administrated daily via intraperitoneal injection after GBM cell implantation, resulting in a significant increase in the median survival time (38 days) of mice.
200 μM (LN229)
100-200 μM significantly reduced the cellular viability of glioma cells (U 251, T98G, and U 87) in a concentration- and time-dependent manner; 100 μM pioglitazone inhibited U 251 cell migration by reduction of MMP-2 expression; 50 μM reduced significantly the metabolic activity of G144 cell lines; 10 μM promoted only a slight decrease of the metabolic activity in GliNS2 cell line. IC90 value reported for pioglitazone was reported to be 158 μM in U 87 cells.
85 μM (U 87)
5–20 μM decreased survival of glioma cells (C6 and U 251) without affecting primary astrocytes; 50 μM had a small effect on the growth of A 172 and U 87 cells; 50 μM produced only a slight and reversible block in the G2/M phase (M059K cells) at 24 h, which was lost by 48 h.
20-30 μM (M059K and M059J)
20 μM was toxic for glioma cells and primary astrocytes; 10 μM was cytoprotective for primary astrocytes but toxic to glioma cells.
100 μM significantly decreased the proliferation of HF2414 GSCs and their self renewal (such effect was also observed at a concentration of 50 μM); phenformin (100 μM) inhibited the expression of the stemness markers OCT4, SOX2 and CD44; phenformin (1 mg/ml) administered orally in mice harboring GSC-derived xenografts for 4 weeks significantly decreased tumor growth (similar results were obtained when phenformin (50 mg/kg/day) was administered by intraperitoneal injection).
Concentrations over 0.5 mM reduced NF-κB activity for prolonged incubation (48 and 72 h); even at low doses (0.25 mM), sulfasalazine was able to suppress glioma growth by over 60%;
Maximum inhibition was reached with aprepitant at 70 μM when no living cells were observed after 48 h of co-culture (GAMG glioma cell line); 15 μM exerted a growth inhibition 6.71 % in that cell line; the IC50 of aprepitant for non-tumor cells is 90 µM, more than two-fold higher than for tumor cells.
32 µM (GAMG)
Significantly decreased growth rates of both U 373 GBM and 9L gliosarcoma cells at concentrations equal or higher than 100 mM; 100 and 1000 nM cimetidine significantly decreased the migration levels of both cell lines; doses between 100 and 0.1 mM induced no modification in either cell cycle kinetics or apoptotic features.
In the range of 0.1–25 μM, estradiol decreased cell viability in a concentration-dependent manner.
3.5 μM (C6)
3.8 μM (T98G)
In U 87 cells, celecoxib (8 and 30 μM) significantly induced DNA damage and inhibited DNA synthesis, corresponding with p53 activation.
150 μM caused a significant increase in G0/G1 and decrease in the S and G2/M populations of glioma cells, reducing as well the migration capability of cells; amlexanox intraperitoneally injected, every day for 21 days, in subcutaneous glioma model using U 87 cells, resulted in inhibitory effect on tumor growth and significantly decreased the tumor volume.
120 μM (U 87)
140 μM (U 251)
1 μM, 5 μM, and 10 μM inhibited proliferation of U 87 and T98G cells in a dose-dependent manner: 1 μM, 5 μM, and 10 μM (with ED50 of 5 μM); ivermectin at 10 μM completely abolished the ability of HBMEC to form tubular structures; the serum concentration of the ivermectin 15 mg/kg administered orally was 33 μM; ivermectin (40 mg/kg) given intraperitoneally during 3 weeks in SCID mouse resulted in notorious inhibition of U 87 and T98G tumors growth. EC50 value for ivermectin was reported to be 5 μM.

MTT: 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; GBM: glioblastoma multiforme; TMZ: temozolomide; TMZR: temozolomide resistant; MMF: mono-methyl fumarate; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand; GSC: glioma stem cells; HIF: hypoxia-inducible factor; FAK: focal adhesion kinase; IC50: half maximal inhibitory concentration; BBB: blood-brain barrier; MMP: matrix metalloproteinase; CLIC: chloride intracellular channel; CSC: cancer stem cell; NF-κB: factor nuclear kappa B; ED50: median effective dose; HBMEC: human brain microvascular endothelial cells; DNA: deoxyribonucleic acid; SCID: severe combined immunodeficiency.

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