What is a "repurposed drug"? What kinds of repurposed drugs are relevant to EGFR-positive NSCLC?

[WORK IN PROGRESS - DESCRIPTIONS HERE ARE INTENDED TO BE BRIEF. MORE IN-DEPTH DESCRIPTIONS CAN BE ON SEPARATE PAGES, AND LINKED TO FROM HERE.]

0 votes

1 answers

1198 views

ANSWER



Drug repurposing is the use of an existing drug whose approved applications are for one disease, to treat another disease [1]. Repurposed drugs are often very much cheaper than cancer-specific drugs, and often (though not always) have much milder side-effects. Large-scale trial evidence is typically lacking for repurposed drugs however, precisely because these drugs are cheaper and there is little profit to be made, and so there is little funding for such trials.

The dividing lines between “drug”, “medicinal herb” and “supplement” can be quite blurred, and somewhat artificial. Broadly, however, it might be said that “drugs” tend to have a more focused mechanism of action than medicinal herbs and dietary supplements, which may contain multiple active compounds and/or target multiple biochemical pathways simultaneously. In terms of effect, medicinal herbs and dietary supplements may often be as powerful as prescription drugs, although herbs and supplements are typically not as well-researched [2]. Given these considerations, this section covers a selection of medicinal herbs and supplements in addition to repurposed prescription drugs. One note of caution is that herbs and supplements are typically not subject to the same quality controls as prescription drugs however.

There is a host of repurposed drugs, herbs and supplements that can potentially be leveraged for lung cancer treatment, EGFR-positive or otherwise:

Artesunate & Artemisinin

Primary Usage

Artesunate is derived from artemisinin, which itself is isolated from sweet wormwood, a herb used in traditional Chinese medicine. Artesunate is now the recommended treatment of the WHO for severe and complicated malaria [1] although it has not yet been approved by NICE in the UK, and the mechanism of antimalarial action of artemisinins is not well understood.

Anticancer Mechanisms

Both artesunate and artemisinin have demonstrated anti-cancer action [2]. Iron and heme metabolism have perhaps the main role in the anticancer activity of artemisinin compounds, although artemisinins appear to exhibit multiple anticancer mechanisms, including inhibition of angiogenesis, proliferation, migration, and VEGF inhibition [3].

Evidence

Mouse experiments have shown that artemisin can inhibit lung cancer tumorigenesis and “perfectly” inhibit metastasis through Wnt/β-catenin signaling, and has high bioavailability and low toxicity [4]. The effect on tumour volume and weight of A549 xenografts was comparable to the TKI afatinib, with much lower toxicity: ArtemisininMouseExperiments A randomised, double-blind, placebo-controlled study of oral artesunate for colorectal cancer with 20 patients (artesunate = 9, placebo = 11, 200 mg oral artesunate, daily for fourteen days prior to surgery) showed that during a median follow up of 42 months 1 patient in the artesunate group and 6 patients in the placebo group developed recurrent cancer [5].

Current Trials

There are no current artesunate or artemisinin trials for lung cancer.

Material Side-Effects & Interactions

Artesunate and artemisinin are generally well tolerated. Side effects of artesunate may include slow heartbeat, allergic reaction, dizziness, and low white blood cell levels [6].

Sourcing

Artemisinin may be straightforwardly purchased online - e.g. on Amazon. Amazon uses third-party suppliers however, so quality may vary; for an approved reseller of Doctor's Best supplements, try iHerb. Artesunate is much more problematic to source, given the high prevalence of counterfeit drugs here [7]. There are many online suppliers, but caveat emptor! Furthermore, artesunate may not be prescribed off-label by a GP in the UK, since NICE has not approved this drug.

 

Aspirin

Primary Usage

Medicines derived from willow trees and other salicylate-rich plants have been widely used for over 4,000 years, first recorded in ancient Sumeria, and then in China and Greece. Aspirin (acetylsalicyclic acid ASA) is derived from salicylic acid, which is the main component of a herbal extract found in willow bark and a number of fruits, grains and vegetables [1]. Aspirin is currently used to treat pain, swelling, fever, inflammation, and recurrence of heart attacks and strokes by thinning the blood [2].

Anticancer Mechanisms

Aspirin inhibits the Cyclooxygenase (COX)-1 and 2 enzymes, reducing inflammation that might otherwise promote cancer growth [3]. Aspirin can also inhibit coagulation of platelets, that might otherwise shield metastatic cancer cells from the immune system [4].

Osimertinib-resistant cells show abnormal activation of PI3K/AKT/BIM. Aspirin can effectively decrease AKT phosphorylation and activate BIM. Thus, aspirin may inhibit the PI3K/AKT/BIM signalling pathways and promote the apoptosis of osimertinib-resistant cells [5].

Aspirin may augment the effects of PD-1/PD-L1 checkpoint inhibitors, since inhibition of COX synergises with anti-PD-1 blockade in inducing eradication of tumours [6].

Evidence

A 2016 meta-analysis of five randomised trials and 42 observational studies on aspirin taken by patients following diagnoses of various cancers found that:

  • Mortality from colon cancer was reduced (HR = 0.76). A mutation of PIK3CA was present in about 20% of patients, and appeared to explain most of the reduction in colon cancer mortality by aspirin.
  • Mortality from breast cancer was reduced (HR = 0.87).
  • Mortality from prostate cancer was reduced (HR = 0.89).
  • Mortality from lung cancer was reduced significantly only after three years (HR = 0.89). One hypothesis here is that treatment-resistant PIK3CA mutations (which are in turn susceptible to aspirin) only developed after an extended period.

See [7] for further details.

Two case reports from 2009 showed that aspirin was effective for treating erlotinib-induced skin rash [8].

A 2016 set of mice experiments found that oral aspirin significantly augmented the anti-cancer action of a PD-1 checkpoint inhibitor, in mice implanted with melanoma cells. COX-1 and COX-2 enzymes are often over-expressed in melanoma, colorectal, breast, stomach, lung and pancreatic cancers, so although the researchers only used melanoma cells these results may carry over to other cancer types [9]. It is notable that aspirin administered by itself had no statistically significant effect in these experiments.

Current Trials

Aspirin is being investigated as a method of combating acquired resistance to osimertinib in the following trials (not yet recruiting; also, it seems likely that these two entries represent the same trial):

https://www.clinicaltrials.gov/ct2/show/NCT03532698

https://www.clinicaltrials.gov/ct2/show/NCT03543683

Other current trials investigating aspirin for lung cancer are:

https://www.clinicaltrials.gov/ct2/show/NCT01707823

https://www.clinicaltrials.gov/ct2/show/NCT02348203

Material Side-Effects & Interactions

Due to its blood-thinning effects, aspirin can increase the risk of bleeding; patients with gastritis, mild diabetes or peptic ulcers should seek medical advice before using aspirin. Aspirin should also not be taken by patients with intolerance to NSAIDS, or who are allergic to ibuprofen. Aspirin also inhibits the excretion of uric acid from the kidneys, and so is contraindicated for patients with kidney disease. See [10] for further details.

Sourcing

Aspirin is readily available over-the-counter in all developed countries.

Administration & Dosage

Aspirin is taken in tablet form.

For the anti-platelet effects of aspirin, 75mg per day over an extended period is sufficient [11].

To treat TKI-induced skin rash, 100mg per day was found to be sufficient [12].

For the anti-inflammatory COX-1 and COX-2 inhibitory effects of aspirin, larger doses are required. To reduce inflammation, doses of 300mg are advised [13].

In order to augment a checkpoint inhibitor, higher doses still may be required. The experiments above used 600 μg/ml in drinking water [14]. The average mouse drinks 4ml water per day and weighs 25g [15]. This gives a daily dose of aspirin per mouse of 2.4mg, or 96mg/kg. Dividing by a mouse->human conversion factor of 12.3 ([16]) gives a human-equivalent dose of 7.8mg/kg per day. For a 70kg adult, this would imply approximately 550mg of aspirin daily. This may need to be restricted to 325mg per day (a standard tablet size) in practice, if taken for an extended period, and even this dose will carry increased risk of the side-effects described above. It is also important to note that murine results may well not carry over to humans.

 

Auranofin

Primary Usage

Analogous to cisplatin (which is a platinum complex), auranofin is a gold(I) complex. Auranofin is used in the treatment of adult rheumatoid arthritis, and can reduce observed symptoms. The mechanism of action of auranofin in this respect is not understood [1].

Anticancer Mechanisms

The primary target of gold complexes like auranofin is not DNA directly, but the alteration of mitochondrial function as well as inhibition of protein synthesis used in maintaining DNA cross-links. Auranofin inhibits redox (reduction/oxidation) enzymes such as thioredoxin reductase (TrxR). TrxR is essential to many cellular processes, such as maintaining the intracellular levels of reactive oxygen species (ROS). Cancer cells over-express redox enzymes, increasing the affinity of auranofin for these cells. Redox inhibition by auranofin causes increased production of ROS that results in cellular stress and apoptosis [2].

However, given the immune-system-suppressing side-effects of auranofin (see section on side-effects below) caution in its use should be exercised.

Evidence

A 2016 paper evaluated auranofin's activity in 10 NSCLC cell lines in-vitro, as well as xenografted NSCLC tumours in mice. Auranofin was observed to elicit apoptosis in aurofin-sensitive cell lines, and was found to significantly suppress tumour growth in the mice with no observed adverse effects [3].

A 2014 paper showed that the combination of selenocystine and auranofin worked synergistically together to target TrxR, demonstrating apoptosis of A549 NSCLC cells in-vitro and in-vivo (mice) [4].

Another 2014 paper demonstrated that auranofin could overcome resistance to the TKI imatinib in myeloid leukemia cells [5].

Current Trials

One current trial is using a combination of sirolimus and auranofin to treat NSCLC and SCLC: https://www.clinicaltrials.gov/ct2/show/NCT01737502.

Material Side-Effects & Interactions

Auranofin can cause gold toxicity. Symptoms of this can include:

  • Falls in haemoglobin, leukocytes, granulocytes and platelets.
  • Elevated liver enzymes.
  • Proteinuria.
  • Pruritis.
  • Rash.
  • Stomatitis.
  • Persistent diarrhea.

See [6] for further details.

Sourcing

Auranofin is available in tablet form under the brand name Ridaura. It was discontinued in December 2009 in the UK so an unlicensed preparation would be required [7], although it may be purchased online (caveat emptor). Given the side effects of auranofin, it is not recommended to take auranofin without the supervision of a medical professional.

 

Captopril

Primary Usage

Captopril is used to manage hypertension and treat congestive heart failure. It is an ACE (angiotensin-converting enzyme) inhibitor, which relaxes blood vessels and decreases blood volume [1].

Anticancer Mechanisms

ACE is an enzyme used in the creation of angiotensin II (Ang II). Ang II in turn promotes angiogenesis through activation of vascular endothelial growth factor (VEGF). Ang II also acts as an anti-apoptotic agent and as a growth factor acting through the EGFR/ERK pathway [2].

Use of ACE inhibitors like Captopril may thus inhibit angiogenesis, promote apoptosis, and reduce cancer growth [3].

However, it should also be noted that ACE inhibitors may impair the immune response to cancer, by augmenting CD4+ T-cell responses (which inhibit an immune response) and impairing the development of CD8+ T-cells (which would otherwise attack cancer cells) [4].

Evidence

Current Trials

Material Side-Effects & Interactions

Sourcing

 

Celecoxib

Primary Usage

Anticancer Mechanisms

Evidence

Current Trials

Material Side-Effects & Interactions

Sourcing

 

Cimetidine

Primary Usage

Cimetidine is used for the treatment of dyspepsia, gastric ulcers and gastroesophageal reflux disease (GERD). It is a histamine H2-receptor antagonist (H2RA; an antihistamine) that reduces the production of gastric acid by blocking the action of histamine on gastric parietal cells [1].

Anticancer Mechanisms

Anticancer action of cimetidine arises from four distinct effects:

  • Anti-proliferative effects. Tumours can secrete high levels of histamine, with action mediated by four histamine receptors, of which H2 and H4 are implicated in cancer cell proliferation, invasion, and angiogenesis.
  • Immunomodulatory effects. Histamine is associated with an immunosuppressive tumour microenvironment.
  • Cell adhesion effects. Cimetidine appears to inhibit the adhesion of some cancer cells, independently of its antihistamine properties, thus inhibiting cancer progression and metastasis.
  • Anti-angiogenesis effects. Production of vascular endothelial growth factor (VEGF) can be mediated by the H2 receptor.

See [2], [3] and [4] for further details.

Evidence

A case report from 1979 gave evidence that cimetidine had regressed the lung cancers of a 52-year-old woman and a 71-year-old man [5]. A further case report in 1982 showed evidence for activity of cimetidine against melanoma in a 34-year-old man and a 45-year-old man, sending both in to remission [6]. A 1995 report on a trial with 64 colorectal cancer patients undergoing surgery demonstrated a 3.9-year survival for colon cancer of 96.3% with cimetidine vs 68% without, and for rectal cancer of 100% with cimetidine vs 53.3% without. 800mg of oral cimetidine was administered daily for 1 year, starting 2 weeks after the operation [7].

A 2002 follow-up report on the same trial demonstrated a 10-year survival of 84.6% with cimetidine vs 49.8% without. In the group with the most aggressive cancers the figures were 85% vs 23% [8].

Current Trials

There are no current cimetidine trials for lung cancer.

Material Side-Effects & Interactions

Side-effects include rashes, fatigue, constipation, muscle pain and diarrhea. However, these side-effects are usually mild and transient [9]. Cimetidine has numerous drug interactions. It is a CYP3A4 inhibitor, and may therefore increase the blood concentrations of TKIs like erlotinib. It also inhibits the renal excretion of metformin [10].

Sourcing

In the UK, cimetidine is a prescription-only drug, but may be prescribed off-label by a GP on presentation of sufficient evidence.

 

Curcumin

Primary Usage

Anticancer Mechanisms

Evidence

[CONFLICTING EVIDENCE SHOULD BE STRESSED HERE. THERE ARE SEVERAL META-ANALYSES AVAILABLE. THE “FAKE RESULTS” CONTROVERSY FROM SOUTH AMERICA SHOULD ALSO BE DETAILED.]

Current Trials

Material Side-Effects & Interactions

Sourcing

[ INCLUDE THE TESTING REPORT DONE BY CONSUMERLAB.COM ON A LARGE SELECTION OF CURCUMIN SUPPLEMENTS. DOCTOR'S BEST COMES OUT ON TOP. ]

 

Disulfiram

Primary Usage

Anticancer Mechanisms

Evidence

Current Trials

Material Side-Effects & Interactions

Sourcing

 

Honokiol

Primary Usage

Honokiol is extracted from the stem bark of the Magnolia obovata tree (“Japanese whitebark magnolia”), a species of Magnolia native to Japan and the adjacent Kurile Islands. It is used in traditional Chinese medicine for treatment of thrombotic stroke, typhoid fever, fever and headache. It has a wide variety of pharmacological effects and biochemical activities [1].

Anticancer Mechanisms

Honokiol affects multiple signaling pathways, molecular and cellular targets including nuclear factor-κB (NF-κB), STAT3, epidermal growth factor receptor (EGFR), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6, cell survival signalling, cell cycle, cyclooxygenase and other inflammatory mediators. In-vitro, honokiol has been shown to inhibit tumour development, progression and migration for a broad range of cancer cell lines [2].

Evidence

No published human experiments have been performed with honokiol. In mice, oral honokiol has been shown to significantly decrease lung tumour growth compared to a control group, significantly reduce the incidence of lymph node metastasis and the weight of mediastinal lymph nodes, and inhibit metastasis of lung cancer cells to the brain to approximately one third of that observed in controls [3]. Honokiol 10 mg/kg appears to be the dose required for efficacy in mice. Following [4] and dividing by 12.3, this implies an equivalent human dose of around 0.8mg/kg, which for a 70kg person implies a dose of approximately 50mg. It should be recognised that murine results very often do not carry over to humans however!

Current Trials

There are no current honokiol trials for lung cancer.

Material Side-Effects & Interactions

Honokiol's limited published empirical application to humans has in turn limited the evaluation of its side-effects. Potential risks include increased bleeding and neurotoxicity at high doses. Honokiol has also been found to be a potent inhibitor of arterial thrombosis, so it may be advisable to avoid honokiol in coagulopathic patients or in those where bleeding or hemorrhage may be of concern [5]. Magnolia bark extract interacts with alcohol, and sedative medications such as barbiturates, benzodiazepines and CNS depressants [6]. There is little hard information available specifically on honokiol's drug interactions, but it has been shown to be only a weak CYP2B6 inducer, and is unlikely to increase the metabolism of concomitant CYP2B6 substrates and cause pharmacokinetic-based drug interactions in humans [7].

Sourcing

Honokiol extract may be sourced online, e.g. from Amazon. Each tablet here appears to contain 250mg of Honokiol, which is approximately five times the does required for efficacy from the mouse experiments. As with most online sources however, there is no solid information available on quality.

 

Itraconazole

Primary Usage

Itraconazole is an antifungal medication. In-vitro studies have demonstrated that itraconazole inhibits the synthesis of ergosterol, which is a vital component of fungal cell membranes [1]. Ergosterol serves many of the same functions in fungal cells that cholesterol serves in animal cells; in this way itraconazole may be seen to be analogous to statins.

Anticancer Mechanisms

An emerging body of in vivo, in vitro and clinical evidence has confirmed that itraconazole possesses antineoplastic activities and has a synergistic action when combined with other chemotherapeutic agents. Itraconazole acts via several mechanisms to prevent tumour growth:

  • Inhibition of the Hedgehog pathway, which is a signalling pathway that regulates adult stem cells involved in maintenance and regeneration of tissues. The pathway has also been implicated in the development of some cancers.
  • Prevention of angiogenesis via binding to VEGF receptors, and so reduced VEGF signalling.
  • Decreased endothelial cell proliferation.
  • Cell cycle arrest.
  • Induction of autophagy, which is the digestion of cellular components that are no longer useful.

See [2] for further details.

Evidence

A phase II study was performed on 23 Stage IV NSCLC patients randomised to either single agent pemetrexed or combined pemetrexed and itraconazole (200 mg daily for 21 day cycles) as second-line therapy. EGFR-positive patients were allowed to receive prior TKI therapy. The study was stopped early because of increasing use of pemetrexed in the first-line setting.

  • At 3 months, 67% of the patients on itraconazole were progression-free, vs 29% on the control arm (p = 0.11).
  • Median PFS was 5.5 months (itraconazole) vs 2.8 months (control).
  • Median OS was 32 months (itraconazole) vs 8 months (control).

There were no evident differences in toxicity between the study arms [3].

Current Trials

Itraconazole is being tested in the neoadjuvant setting in Texas: https://clinicaltrials.gov/ct2/show/NCT02357836. Itraconazole is being tested in conjunction with rifampin and PF-02341066 in a range of sites: https://clinicaltrials.gov/ct2/show/study/NCT00585195.

Material Side-Effects & Interactions

Itraconazole is generally well-tolerated, but side-effects can include congestive heart failure, decreased gastric acidity, hearing loss, and liver damage. Itraconazole should not be used during pregnancy except in life-threatening cases [4]. Itraconazole is mainly metabolised through the CYP3A4 pathway, so drugs that inhibit this pathway (e.g. cimetidine) may increase the effects of itraconazole.

Sourcing

In the UK, itraconazole is a prescription-only drug, but may be prescribed off-label by a GP on presentation of sufficient evidence.

 

Luteolin

Primary Usage

Luteolin is one of the most common flavonoids present in edible plants, and plants used in traditional medicine [1]. It is used as an anti-inflammatory, in allergies, in asthma and as an anti-pruritic [2].

Anticancer Mechanisms

Luteolin exerts remarkable tumour-suppressive activity on various types of cancers, including NSCLC. Luteolin may inhibit tumorigenesis and induce apoptosis of NSCLC cells by upregulation of miR-34a-5p (a vital part of the p53 tumour suppressor network) via targeting MDM4, leading to increased expression of p53 [3].

Luteolin is also an anti-oxidant, an anti-inflammatory, an anti-proliferative, and an inhibitor of EGFR and TNFα [4].

Evidence

A 2014 paper found that luteolin overcame erlotinib-resistance in EGFR-positive L858R/T790M NSCLC. In mice, 10mg/kg of oral luteolin was found to be as effective as cisplatin, and (unlike cisplatin) had no observed side-effects [5].

Current Trials

Material Side-Effects & Interactions

Sourcing

 

Mebendazole

Primary Usage

Anticancer Mechanisms

Evidence

Current Trials

Material Side-Effects & Interactions

Sourcing

 

Melatonin

Primary Usage

Melatonin is used as a sedative, to reset the internal body clock (e.g. in cases of jet-lag), or to treat insomnia. Melatonin is a hormone that is produced by the pineal gland in the brain, and levels naturally vary in 24 hour cycles which are controlled by our body clock [1].

Anticancer Mechanisms

There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. There is a large number of processes by which melatonin reportedly restrains cancer development and growth, which may be secondary processes of an underlying more fundamental action of melatonin that remains to be discovered [2]. Melatonin may also act to stimulate the immune system [3].

Evidence

A 2003 study compared chemotherapy alone with chemotherapy and 20mg nightly oral melatonin in 100 Stage IV NSCLC patients:

  • A complete response (CR) was achieved in two of 49 (4%) patients in the melatonin group, and 0% in the control group.
  • A partial response (PR) was achieved in 15 of 49 (31%) patients in the melatonin group, and nine of 51 (18%) in the control group.
  • A 5-year survival was achieved in three of 49 (6%) patients in the melatonin group, whereas no patient in the control group was alive after 2 years.

See [4] for further details. A meta-analysis analysed 8 randomised controlled trials (RCTs) of late-stage cancers with a total sample size of 761, each using 20mg oral melatonin daily:

  • CR and PR was 32.6% in the melatonin groups, vs 16.5% in the controls.
  • 1-year survival was 52.2% in the melatonin groups, vs 28.4% in the controls.

See [5] for further details.

Current Trials

Material Side-Effects & Interactions

Sourcing

 

Metformin

Primary Usage

Anticancer Mechanisms

Evidence

A 2017 meta-analysis of 10 studies analysing the effect of metformin treatment on diabetic lung cancer patients found that:

  1. Median PFS improved by 23%.
  2. Median OS improved by 47%.

See [x] for further details.

Another 2017 cohort study analysing the effect of metformin treatment of 636 diabetic NSCLC patients from the US Military Health System (MHS) with a mean follow-up time of 14.6 months found that:

  1. There was a 24% reduction in all-cause mortality per year in this period.
  2. Benefits were greater for longer duration of metformin use., and were only observed in patients who used metformin before cancer diagnosis.
  3. Benefits were restricted to early-stage patients.

See [x] for further details. A 2015 randomised controlled trial of metformin in 30 non-diabetic patients with stage IV NSCLC (15 patients receiving intravenous gemcitabine/cisplatin together with 500mg oral metformin daily, vs a control of 15 patients receiving intravenous gemcitabine/cisplatin alone) found that:

  1. Median PFS was 5.5 months in the metformin group, vs 5 months in the control group (p=0.062). In other words, no effect.
  2. Median OS was 12 months in the metformin group, vs 6.5 months in the control group (p=0.119). A non-statistically significant improvement, although the sample size was small.
  3. ORR was 46.7% in the metformin group, vs 13.3% in the control group.

See [x] for further details. The OS Kaplan-Meier curve is below. Although not statistically significant due to the small sample size, it is worth noting the doubling in 1-year survival:

No large-scale human trials have been reported with metformin in NSCLC, although many are in progress. Interim results from an ongoing randomised Phase II trial of metformin use in 139 non-diabetic EGFR-positive stage IV NSCLC patients were published at ASCO 2018. 69 patients took 500mg oral metformin daily in conjunction with their TKI, whereas 70 patients took a TKI alone. Analysing results to December 2017, the study found:

  1. Median PFS with metformin was 13.1 months, vs 9.9 months in the control group.
  2. Median OS with metformin was 31.7 months, vs 17.5 months in the control group.

See [x] for further details.

Current Trials

Several trials are currently recruiting for metformin use in lung cancer. The last one in the list here corresponds to the TKI study above. https://www.clinicaltrials.gov/ct2/show/NCT02115464 https://www.clinicaltrials.gov/ct2/show/NCT03086733 https://www.clinicaltrials.gov/ct2/show/NCT03048500 https://www.clinicaltrials.gov/ct2/show/NCT03071705

Material Side-Effects & Interactions

Sourcing

 

Mifepristone

Primary Usage

Anticancer Mechanisms

Evidence

Current Trials

Material Side-Effects & Interactions

Sourcing

 

Nitroglycerin

Primary Usage

Anticancer Mechanisms

Evidence

Current Trials

Material Side-Effects & Interactions

Sourcing

 

Propranolol (& Other Non-Selective Beta Blockers)

Primary Usage

Anticancer Mechanisms

Evidence

Current Trials

Material Side-Effects & Interactions

Sourcing

 

Ritonavir

Primary Usage

Anticancer Mechanisms

Evidence

Current Trials

Material Side-Effects & Interactions

Sourcing

 

Sertraline

Primary Usage

Sertraline is a SSRI (Selective Serotonin Reuptake Inhibitor) that is used as an antidepressant [1]. Although the exact mechanism of action of SSRIs is unknown, they are believed to increase the extracellular level of serotonin in the brain by limiting its reabsorption [2].

Anticancer Mechanisms

Sertraline may work synergistically with TKIs via promoting autophagy of NSCLC cells [3].

However, there is some evidence that SSRIs may be immunosuppressive [4].

Evidence

A 2018 set of experiments in mice showed that sertraline inhibited the viability of NSCLC cells and showed a synergy with erlotinib, promoting increased survival and inhibiting NSCLC cell growth [5].

Current Trials

There are no current sertraline trials for lung cancer.

Material Side-Effects & Interactions

Sertraline can cause moderate nausea and sexual dysfunction, and fatigue, dry mouth and insomnia [6], [7].

Sourcing

In the UK, sertraline is a prescription-only drug, but may be prescribed off-label by a GP on presentation of sufficient evidence.

 

Silibinin (Legasil)

Primary Usage

Silbinin (aka silybin) is present in the silymarin extract of milk thistle seeds. Milk thistle is used to treat liver disorders [1], and also by nursing mothers to increase milk production [2]. Silibin is used in the treatment of chronic liver disease [3].

Anticancer Mechanisms

STAT3 (Signal Transducer and Activator of Transcription 3) signalling has been shown to be important in brain metastasis [4]. Silibinin crosses the BBB and impairs STAT3 activation in the tumour microenvironment [5].

Silibinin has also been shown to have activity against NSCLC cells more generally, possibly because it is an EGFR inhibitor [6].

Silibinin may also help to prevent resistance to TKIs, since it is an EMT (Epithelial-to-Mesenchymal Transition) inhibitor [7].

Evidence

In a July 2018 Nature paper, 18 patients with NSCLC brain metastases were treated with silibinin (in the form of the proprietary Legasil formulation). Legasil was used either as a single agent (3 patients under palliative care) or in combination with additional chemotherapy (15 patients). Legasil reduced brain metastasis by at least 30% in 75% of the patients and eliminated metastasis in 20% of patients. The treatment extended the median survival time of the patients to 15.5 months compared with an average of 4.0 months in patients with brain metastasis who received only standard treatment. The 3 patients who started to take Legasil under palliative care received additional lines of chemotherapy when their general status improved and central nervous system responses were confirmed by magnetic resonance imaging (MRI) [8].

In a 2013 set of experiments in mice, oral silibinin decreased the volumes of NSCLC tumours as efficiently as gefitinib, and concurrent treatment with silibinin impeded the regrowth of gefitinib-resistant tumors, resulting in “drastic tumour growth prevention” [9]. A different form of silibinin was used here: silibinin was combined with the common excipient meglumine in order to increase bioavailability. However, Legasil has also been formulated so as to increase bioavailability, so in practice there may be little to choose between the two.

Current Trials

One trial is evaluating the usage of silibinin in lung cancer, in conjunction with erlotinib, but its current status is unknown:

https://clinicaltrials.gov/ct2/show/NCT02146118?term=silibinin&rank=7

Material Side-Effects & Interactions

Silibinin does not show significant interactions with other drugs and at doses under 10 g/d has no significant side effects [10].

Sourcing

Legasil is readily available online - e.g. https://www.parafarmaciacampoamor.com/en/170182-legasil-30-tablets.html - and over the counter from Spanish pharmacies. The link given here is to a reputable online chemist.

In China, silibinin meglumine (the form of silibinin combined with the excipient meglumine) is available on prescription.

Administration & Dosage

Legasil is taken in tablet form.

1g daily (two 500mg Legasil tablets) was used in the July 2018 Nature paper [11].

 

Statins

Primary Usage

Statins are used to lower cholesterol and reduce cardiovascular disease and mortality. Their mechanism of action is to inhibit “HMG-CoA reductase”, a rate-limiting enzyme for the “mevalonate pathway”, mevalonate being a molecule in a chain of processes that produce cholesterol. In other words, statins decrease mevalonate production, which in turn decreases cholesterol production [1].

Anticancer Mechanisms

The exact anticancer mechanisms of statins remain unclear. In in-vitro experiments, statins exert different effects depending on cell line, statin concentration, duration of exposure of cells to statins, and the type of statin being used. The following effects have been observed:

  • Cell cycle inhibition by influence on both expression and activity of proteins involved in cell-cycle progression such as cyclins, cyclindependent kinases (CDK), and/or inhibitors of CDK.
  • Induction of apoptosis by both intrinsic pathways (mediated by changes in mitochondria) and extrinsic pathways (mediated by tumour necrosis factor alpha “TNF-alpha”).
  • Changes in biochemical pathways downstream of EGFR, mainly via inhibition of the mevalonate pathway.
  • Destabilisation of cell membranes by cholesterol synthesis inhibition.

See [2] for further details. When targeting CNS metastases with statins, lipophilic statins are to be preferred as they can more easily cross the blood-brain barrier. The most lipophilic statin is simvastatin, with lovastatin, atorvastatin and fluvastatin also being lipophilic [3].

Evidence

A nationwide, population-based case-control study in Taiwan was conducted using the Taiwan National Health Insurance Research Database. From January 1, 1997 to December 31, 2012, a total of 1,707 statin and 6,828 non-statin matched lung cancer cohorts with EGFR-TKIs treatment were studied. Statin use was associated with a significantly longer median PFS (8.3 months vs 6.1 months) and median OS (35.5 months vs 23.9 months) [4]. Statins_OSTaiwan Another nationwide, population-based case-control study in South Korea was conducted using Korea’s National Health Insurance Service Database. Patients ≥ 70 years old with advanced NSCLC incident from 2007 to 2012 were identified, and exposures to statin and/or metformin were also documented. Use of statin, regardless of metformin, was associated with improved median OS (14.5 months for statin+metformin, 12.9 months for statin-metformin, and 9.9 months in the control group) [5 - TO BE PROVIDED FROM 2018 ASCO BY LARS].

Current Trials

A single trial is recruiting for use of statins with lung cancer, used in combination with chemotherapy: https://www.clinicaltrials.gov/ct2/show/NCT01441349.

Material Side-Effects & Interactions

Statins have a very good safety profile, but side-effects can include nausea, diarrhea, constipation and muscle necrosis, liver damage, insomnia and other CNS effects. There is no evidence for kidney damage. Lovastatin, simvastatin and atorvastatin are metabolised by the CYP3A4 pathway while rosuvastatin and fluvastatin are metabolised by CYP2C9. Thus, inhibitors of these pathways (e.g. grapefruit juice, and indeed other drugs in this section) may increase the activity of these statins. [6]

Sourcing

In the UK, statins are prescription-only drugs, but may be prescribed off-label by a GP on presentation of sufficient evidence.

 

Tetrathiomolybdate

Primary Usage

Anticancer Mechanisms

Evidence

Current Trials

Material Side-Effects & Interactions

Sourcing

 

Thalidomide

Primary Usage

Anticancer Mechanisms

Evidence

Current Trials

Material Side-Effects & Interactions

Sourcing

 

Vitamin C

Primary Usage

Anticancer Mechanisms

Evidence

Current Trials

Material Side-Effects & Interactions

Sourcing

 

Vitamin D

Primary Usage

Anticancer Mechanisms

Evidence

Current Trials

Material Side-Effects & Interactions

Sourcing

FILES:   BetaBlockers_NSCLCProliferation.pdf   BetaBlockers_Overview.pdf   Propranolol_Leaflet.pdf   Sertraline_Image1.png   Sertraline_NSCLCAutophagy.pdf   SSRI_Immunosuppressive.pdf   SSRI_SideEffects.pdf   SSRI_mechanisms.pdf   Antidepressant_LungCancerSurvival.pdf   Sertraline_PatientLeaflet.pdf   Silibinin_Image2.png   Silibinin_EMTInhibitor.pdf   Silibinin_EGFRInhibitor.pdf   Silibinin_SideEffects.pdf   Silibinin_TreatsNSCLCBrainMetastases.pdf   STAT3.pdf   Silibinin_NatureHighlight.pdf   Silibinin_Image1.png   Silibinin_LiverDisease.pdf   MilkThistle_Uses2.pdf   MilkThistle_uses.pdf   Beta blocker use correlates.pdf   Luteolin_AntiCarcinogenicEffects.pdf   Luteolin_Image2.png   Captopril_AngiotensinSystem.pdf   Captopril_ImpairsImmuneSystem.pdf   CaptoprilPotentialInhibitorLungTumourGrowthMetastasis.pdf   Captopril_InfoLeaflet.pdf   Aspirin_CellExtended.pdf   Luteolin_OvercomesErlotinibResistanceInL858R_T790M.pdf   Luteolin_Image1.png   Luteolin_InhibitsTumorigenesisAndInducesApoptosisNSCLC.pdf   Luteolin_AntiCancerOverview.pdf   Luteolin_BiologicalActivities.pdf   Luteolin_Uses.pdf   Auranofin_NHSLeaflet.pdf   Auranofin_MiceImage3.png   Auranofin_MiceImage2.png   Auranofin_MiceImage1.png   Auranofin_PrescribingInformation.pdf   Auranofin_OvercomesImatinibResistance.pdf   Auranofin_LungCancerInVitro.pdf   Auranofin_2018NaturePaper.pdf   Auranofin_LungCancerInVivo.pdf   Auranofin_Repurposing.pdf   Aspirin_COXInhibitionImage.png   Aspirin_TurnOfTheCenturyMiracleDrug.pdf   Aspirin_AugmentsCheckpointInhibitors.pdf   Aspirin_TKISkinRash.pdf   Aspirin_PatientInformationLeaflet.pdf   Aspirin_Antiplatelet.pdf   Aspirin_MechanismAntiCancer.pdf   Aspirin_MetaAnalysis.PDF   Metformin_KaplanMeier3.png   Metformin_WithTKIPresentation.pptx   Metformin_KaplanMeier2.png   Metformin_Trial.pdf   Metformin_CohortStudy.pdf   Metformin_KaplanMeier1.png   Metformin_DiabetesMetaAnalysis.pdf   Melatonin_MetaAnalysis.pdf   Melatonin_ImmuneSystem.pdf   Melatonin_Uses.pdf   Melatonin_Mechanisms.pdf   Melatonin_KaplanMeier1.png   Melatonin_Study1.pdf   Itraconazole_SideEffects.pdf   Itraconazole_KaplanMeier2.png   Itraconazole_KaplanMeier.png   Itraconazole_Phase2Study.pdf   Itraconazole_RepurposingReview.pdf   Itraconazole_MedicationInfo.pdf   Statins_BenefitsRisks.pdf   Statins_Lipophilic.pdf   Statins_OSTaiwan.png   Statins_ImproveEGFRSurvival.pdf   Statins_EffectsOnCancerCells.pdf   Statins_CardiovascularDiseasePrevention.pdf   MedicinalHerbs.pdf   Honokiol_DrugMetabolisingEffects.pdf   Honokiol_Review.pdf   MouseHumanDosing.pdf   Honokiol_TumourGrowthImage.png   Honokiol_InhibitsLungCancerMetastasis.pdf   Honokiol_AntiInflammatoryNutraceuticalsAndChronicDiseases.pdf   Honokiol_PharmacologicalFeatures.pdf   Cimetidine_Interactions.pdf   Cimetidine_KaplanMeier.png   Cimetidine_ColorectalCancer0.pdf   Cimetidine_ColorectalCancer.pdf   Cimetidine_CaseReport1.pdf   Cimetidine_CaseReport2.pdf   CancerCellAdhesionAndMetastasis.pdf   Cimetidine.pdf   Cimetidine_AnticancerDrug.pdf   Cimetidine_AntiCancer.pdf   Artesunate_PackageLeaflet.pdf   Artesunate_Fake.PDF   ArtemisininVsAfatinib_Image.png   Artemisinins_TheirGrowingImportanceInMedicine.pdf   Artesunate_Malaria.pdf   Artemisinin_LungCancer_MiceExperiments.pdf   ArtemisininCompounds_AnticancerEffect.pdf   ArtesunateTrial_ColorectalCancer.pdf   NewUsesForOldDrugs.pdf
0 votes