ALLERGY, DRUGS & CLINICAL IMMUNOLOGY (ADCI)

Therapeutic Links between Anti-Cancer Drugs and Alzheimer’s Disease: A Review



Krishna Prasad Pathak1,Tara Gaire2,Magda Tsolaki3*


1,2Star Hospital Lalitpur, Nepal
33rd Department of Neurology, Aristotle University of Thessaloniki, Greece

*Corresponding Author:Dr. Magda Tsolaki, Professor of Neurology, Neuropsychiatrist, 3rd Department of Neurology of Aristotle University of Thessaloniki, Chair of Greek Federation of Alzheimer's, Greece, TEL::+306942918933 ; FAX::+306942918933;E-mail:tsolakim1@gmail.com


Citation:Krishna Prasad Pathak, Tara Gaire, Magda Tsolaki (2017) Therapeutic Links between Anti-Cancer Drugs and Alzheimer’s Disease: A Review. Allergy drugs clinimmunol1:105.


Copyright:© 2017 Magda Tsolaki, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited


Received date: May 03, 2017; Accepted date: June 10, 2017; Published date: June 14, 2017


Abstract

Background: Cancer is a disease which affects the elderly, just like Alzheimer’s Disease (AD) which is also a common disease affecting older people. Most of the symptoms are related with both these diseases, therefore there may be therapeutic link between anticancer drugs and AD. Little is known (by the way of support of animal model studies) whether anticancer drugs may help to reduce cognitive impairment, reduce Aβ protein, decrease amyloid plaques and promote neuroprotection. There is not sufficient evidence cognitive dysfunction impacts quality of life and compliance for treatment, so assessing the elderly cancer affected population is a challenge in clinical practice for distinguishing between AD symptoms and cancer and its proper treatment.


Objective: To synthesize the studies aimed at therapeutic links between Alzheimer’s disease and anticancer drugs.


Design: To identify potential new treatment possibilities we applied the systematic searches of key electronic databases, supplemented by hand searches of reference lists. Relevant articles were searched for on the following databases: PubMed, Psych Info, Medline, Scopus, Google Search engine, Cochrane library. The inclusion criteria were; (1) Studies aimed at improving cancer and anticancer therapies with human model (2) Peer-reviewed and written in English without any searching limitation on the basis of published date (3) Studies of drugs related to cancer treatment that were relevant to AD. (4) We did not include the clinical news, case report and animal trial studies.


Results: We yielded 45,366 papers. These papers were reduced after filtering titles, abstract, references published in English into one study that has been condensed into one volume of literature. There is very hard to find studies aimed at therapeutic links between Alzheimer’s disease and Anti-cancer drugs (bexarotene) in human model. However, sufficient studies are conducted with animal model (mice) and indicating the positive benefits to the AD patients. Bexarotene is useful for the reduction of cholesterol, loss of function associated with APOE ε4, peripheral thyroid hormone metabolism and athyreotic and amyloid beta that is a key cofactor of Alzheimer’s disease. Also, Bexarotene has been shown to restore cognitive functions. Bexarotene is a compound chemically related to vitamin A that activates Retinoic X Receptors (RXR) found everywhere in the body and rapidly cleared amyloid plaques from the brains of Alzheimer’s model mice.


Conclusion: This review discusses the emerging role of anticancer-drugs-Bexarotene in a clinical trial of Alzheimer’s dementia with the support of animal model successful results and their effectiveness. Cancer drugs are not a miracle cure for AD- dozens of questions have been raised, however, Bexarotene (chemotherapy) improves cognition and other symptoms that appear with AD patients and will be a significant drug in the coming decades.


Keywords: Anti-cancer therapy, Alzheimer’s disease (AD), dementia

Introduction

Cancer and Alzheimer’s disease are associated with aging [1] and are becoming more common. Cancer is one of the most dreaded non-communicable disease and the important contributor to the global burden of diseases as well as one of the leading causes of death worldwide. It is among the leading cause of death worldwide, with approximately 14 million new cases and 8.2 million cancer-related deaths in 2012 [2] Cancer brings tremendous social distress, physical & psychological suffering, hardship to patients and their relatives. The relationship between dementia and cancer is complex [3] to define due to the overlapping characteristics. It has an inverse relationship and most cases are underdiagnosed. Individuals with cancer and dementia demonstrate unique challenges due to poor communication difficulties, mild cognitive impairment and 'chemo brain', progressive neurodegeneration, and cognitive function etc. Therefore, quality assessment is necessary, including cognitive function for both dementia and cancer patients [4].


Likewise, AD has no gold standard treatment (with an overall failure rate 99.6%) [5] like cancer does. This means there are several drugs presently in trials and have shown promise as possible modifiers of disease progression [6]. However, anticancer chemotherapy often induces peripheral neuropathy and as a consequence cognitive decline and finally quality of life is impaired. Commonly anti-epileptics or anti-depressants are recommended, but their efficacy is not satisfactory [7]. Going forward, whether anti-cancer therapy can reverse AD remains to be scientifically proven. No cure exists for AD, but scientists are showing new alternative ways in animal studies- those show that cancer drugs are able to reduce neurodegeneration, raising the possibility of repurposing those agents for use in ΑD. It is found that drugs which reach the brain, took the role of tau stabilized microtubules in the animals’ brains. This led the scientists to conclude that the molecules from these classes could be appropriate drug candidates for treating AD and related disorders [8].


In 2013, Kemsley showed Apolipoprote in ε4 (APOE ε4) and APOE ε3, increased memory power with the use of Bexarotene. Bexarotene is a compound chemically related to vitamin A that activates Retinoic X Receptors (RXR) found everywhere in the body and rapidly cleared amyloid plaques from the brains of Alzheimer’s model mice [4].


The next study’s aim was to assess (within 20 population) the safety and effects on the brain for the drug Bexarotene as a possible treatment for AD. People were given either 300 mg of the anti-cancer drug Bexarotene or a placebo for 1 month and underwent brain scans to determine the drug's effectiveness on the brain. Bexarotene acts to reduce harmful beta-amyloid protein deposits in the brain in experimental models of AD by inhibiting retinoid X receptors, nuclear receptors that have been linked to numerous metabolic pathways relevant to AD and beta-amyloid production and removal [9].


A recent study found that an anti-cancer drug was effective in reversing the memory deficits in an AD mouse model. Bexarotene, which commonly used to fight lymphoma, significantly improved the cognitive deficits in mice expressing gene mutations linked to human AD. They believe that these findings make a solid case for continued exploration of Bexarotene as a therapeutic treatment for AD. Mice treated with Bexarotene-a retinoid approved to treat skin problems caused by T-cell lymphoma- recovered from AD. Mice rapidly gained in intelligence while plaque in their brains, causing the disease began within hours to disappear, boosting levels of Apolipoprotein E that helps clear build-up of amyloid plaque in the brain [10].


Likewise next study [11] claimed that skin cancer drugs treat late-stage dementia in Mice. Scientists declared that a mouse is the best animal model to show the hints of improvement in AD. The genetically engineered mouse carries a human gene that increases the risk of AD by 15 times. Researchers explained that humans generally carry a gene of Apolipoprotein E in cells, which helps to clear amyloid-beta in the brain by binding it and destroying it. One study revealed a 40 percent decrease in levels of soluble amyloid-beta and an increase in the binding of Apolipoprotein in amyloid-beta in mice at the later stages of AD.


Kopman [12], suggested that a cancer drug is not a miracle cure for AD [12] but there is still some hope between Bexarotene and AD. They tested Bexarotene on mice to assess the effects on the brain, especially on AD plaques. The result showed that beta amyloid plaques in the brain were reduced. While mice with Alzheimer's-like brain damage were given Bexarotene orally, they were able to reverse cognitive and social deficits and clear more than half of the beta-amyloid peptides from the brain within 72 hours [13]. Bexarotene, in the current practice showed a great evidence to bring the greater rate of clearance of ß-amyloid plaques over the time significantly [14] and result was based on murine model of AD.


There is another study Bexarotene resulted a significant reduction in the level of the neurotoxic amyloid- beta in the late-stages of AD for mice [15]. In adult patients, cancer brain toxicity remains a major cause of morbidity. Additionally, drugs used in non-brain tumours are now recognized to impair the normal functioning of brain [16]. A review on efficacy and safety of pharmacotherapy in cancer-related psychiatric disorders across the trajectory of cancer care concluded that 25–30% of patients with cancer in an advanced phase of illness met the criteria for a psychiatric disorder like; depression, anxiety, stress-related syndromes, adjustment disorders, sleep disorders and delirium. A review study, on psycho-oncology research has shown the efficacy of psychotropic drugs as adjuvant treatment of cancer-related symptoms, e.g.; pruritus, nausea and vomiting, pain, hot flashes, fatigue, and cognitive impairment, etc [17].


Another study [18] showed the therapeutic positive link between AD and cancer patients, who were survivors of breast cancer and using cancer drugs-s had a lower risk of AD after using anti-cancer drugs. Likewise, a landmark paper was published in Science showed Bexaro¬tene, to treat cutaneous T-cell lymphomas, created potential new hope for the treatment of AD [19]. Additionally, next two studies [20,21] agreed that cancer survivors had a lower risk of AD than those without cancer, and patients with AD had also a lower risk of cancer.


We see the association between AD and cancer on the clinical praxis of symptoms. Likewise One study showed a result of breast cancer of woman who received adjuvant chemotherapy had a higher likelihood of dementia after long-term follow-up [22]. These findings shed light on a cure and warrants analysis of the consequences of this hypothesis, not only from the viewpoint of drug discovery for new treatments, but above all, the awareness that any AD chemotherapy will require drug administration over longer periods of time before any cognitive effects are observed. Because such drugs will probably act as neuro protective agents, slowing the progression of AD rather than curing it, they should be prescribed as soon as the first AD symptoms are detected. After conducting a preliminary survey of anticancer therapy that have potential value for AD, new drugs that affect specific signal transduction pathways known to be activated by anticancer drugs could be identified, with the unfolding protein response pathway being one of the most relevant biological targets for new AD chemotherapeutic agents.


Most AD criteria are based on dysfunction of cognitive ability as well as a significant impact on social functioning and activities of daily living. Conducted human model research with cancer is showing significant proof of the minimising effects of cognitive impairment. The majority of the above-mentioned mice studies do not necessarily translate to human models. Further, animal model research requires for more testing, but the human benefits of Bexarotene and AD are still years away. Some human studies for those with cancer and treated with chemotherapy have shown positive signs in cognitive improvement and some of those animal (mouse) model studies conducted in mice also show positive signs of cognitive improvement [23]. Much research remains to be done, but even if, Bexarotene (chemotheraphy) is found to be effective at reducing cognitive impairment as a treatment for AD in humans, it has opened the door to find a new treatment approach to the pathology of this disease and, in fact, may one day represent a new class of AD therapies. Dozens of questions have been raised, however these must be addressed in a coming study- how does Bexarotene (chemotherapy) improve cognition and other symptoms that appear with AD patients?


The present review is a systematic review of anti-cancer drug and AD aimed at improving the AD related symptoms with the patients. Before this review, a review conducted to describe and discuss the literature addressing the effects of Bexarotene in AD model of mice and showed its potential clinical implications [24]. But we only focus on human model studies in this review. We took a broader review and do not restrict it to any studies with cancer and AD related symptoms. All the aforementioned original studies focus on animal model to measure the effectiveness, often find that the evidence is somewhere mixed or somewhere positive, and provide clues for future AD agent. Furthermore, most cancer patients who were consuming chemotherapy was seen significant to increase the memory issues. That is why, the review worked to find an emerging model of research synthesis “realist review” [25,26], which is designed to work with complex relationships between Alzhemier’s and cancer drugs, and which is aimed at penetrating what drugs, to whom, in what circumstances, in what respects and how.


Additionally, many pharmaceutical companies have downsized the option for new Alzheimer’s treatments after the false step of several eminence exorbitant trials. It was essential to do review study, since last decades there has been the failure rate (99.6%) [5] in AD treatment. This, however, might have a proposed a trend of exploring drugs that have already been approved by the US Food and Drug Administration for other hints, but that can be interacted with physiopathology through mechanisms unrelated to their original therapeutic indication. Since Bexarotene (chemotherapy) have already gone through clinical practice trials or pipeline, which can break through in the AD patients [24].


Likewise, researcher and scientists from Britain and Sweden have hope to be identified future drugs to protect the brain from Alzheimer's disease, by acting proactively as statins, so is called "nefrostatini". A study was conducted lead by the supervisory of the US Food and Drug Administration (FDA), for the treatment of lymphoma. This research was done in by the department of chemistry at the University of Cambridge Michele Ventrouskolo, cultured nerve cells in the laboratory and in nematode worms- found that this substance prevents the first stage of brain cell death. At the initial phase the essence of bexarotene had tested again against the disease without success, but now clinical trials have been focusing on the approach of administration, when longer the disease had progressed and were formed toxic plaques of amyloid protein in the patient's brain [27].


Objective

To synthesize the studies aimed at therapeutic links between Alzheimer’s disease and anticancer drugs.


Methods

Search Strategy: The aim of this systematic review was to retrieve the studies that are related to cancer drug with dementia and AD and to ascertain whether any improvement exists in AD patients’ results. Relevant articles were retrieved following searches of databases: PubMed, PsychInfo, Medline, Scopus, Google search engine, Cochrane library. Titles and abstracts were examined, and then full texts were retrieved for potentially relevant studies and these were assessed. As this is the first systematic review undertaken to evaluate the existing evidence on the therapeutic link between cancer drugs and AD, the search strategy used a broad brush approach using overarching terms/keywords. The use of overarching terms/ keywords ensured that all potentially relevant articles were included in the initial screening. To identify potential new treatments we applied the following: Anti-cancer drugs and dementia, anti-cancer and AD, Anti-cancer and cognitive, chemotherapeutic agents and Alzheimer, Breast cancer and Cognitive impairment, Cancer and language impairment, Cancer and language praxis, Bexarotene and gastrointestinal complication, Cancer drugs and language impairment, Bexarotene and pain, Cancer drugs and cognitive, doxorubicin and Alzheimer, Cancer drugs and dementia, Cancer drugs and AD, Cancer drugs and Apolipoprotein, Liver cancer and lipoprotein, Chemotherapy and dementia, Chemotherapy and Alzheimer disease, Bexarotene and Alzheimer disease, Cancer therapy and Alzheimer Cochrane, Anticancer drugs and dementia, doxorubicin and Alzheimer, Anticancer drugs and cognitive impairment, Chemotherapy drugs and cognitive impairment, Cancer therapy and Alzheimer, Cancer drugs and Alzheimer, Cancer drugs and dementia, cyclophosphamide and Alzheimer, Anti-cancer and cognitive impairment, Chemotherapy and dementia. In all databases, the search was restricted to articles where the keywords were the major focus of the article. A similar search strategy was used in the remaining databases. In addition, we reviewed the reference lists of previous reviews to identify potentially eligible studies. Publication studies were included to any active cancer treatment e.g.; chemotherapy, breast cancer, cognitive deficit, brain cancer, cervical cancer, hormonal therapy and therapy with molecular-targeted agents and any combinations of cancer which were related with AD symptoms and treated with cancer drugs. We did not include those studies showing significant results to the AD patients on the basis of (mice) animal model, online news, case studies, uncompleted experimental studies and their expectation results. Figure 1. And table 2 is describing the some related studies (case studies, uncompleted experimental studies and their expectation results) with Bexarotene because that will be helpful to understand to the reader how it is very close for new treatment of AD.


Figure 1
Figure 1: A diagram of the database search for data based articles on the therapeutic links between Anti-cancer drugs and Alzheimer Disease (AD) treatments.

Results

Included Studies and Characteristics

The broad all above mentioned searches yielded 45,366 citations, those were reduced after filtering titles, abstract, references published in English. Once the abstracts were reviewed for relevance, duplicate publications removed. This systematic review has established that there is very little literature (N=2) published in this area up to now. The inclusion criteria in this study was identified a dearth of treatment based on cancer and symptoms of AD. This systematic review identified just (N=2) one study and illustrated in the table 1. The study was measured the cancer treatment patients and showed a positive result in reducing the common symptoms between cancer and AD. That study was from France and a summary of the study abstract is displayed in the table text. This study adds that the Bexarotene helped to improvement in cognitive impairment, reduced cholesterol levels, pulmonary metastases, thyroid functions and hypothyroidism in the patients who were consuming the Beaxarotene. Maximum studies were conducted with animal studies (mice model) and some were published as current news on online news but we did not included in our study however we have shown these studies in table 2 that might be fruitful as a witness to show the possibility of Beaxarotene in the coming days. Likewise, the next study showed there was a significant association between increased serum Aβ1-42 and reductions in brain amyloid in ApoE4 non-carriers (not in carriers). There were significant elevations in serum triglycerides in Bexarotene-treated patients. There was no consistent change in any clinical measure [28]


Table 1: Characteristics of study.


Study Aim Participant title Study design and methods Results Conclusion
Jacques Fantini et al., 2014, France To find combination of Bexarotene combination and Alzheimers’Amyloid Peptides. Not stated Bexarotene blocks calcium-permeable ion channels formed by neurotoxic Alzheimer’s β-amyloid peptides. It is The experimental approach. it’s combination of molecular, physicochemical, and cellular approaches to elucidate the mechanisms underlying the anti-Alzheimer properties of Bexarotene in neural cells. Bexarotene and cholesterol interact with the same region located in C-terminal domain of Aβ1−42 and share the same binding site on Aβ. Cholesterol, and amyloid beta a key Cofactor of Alzheimer’s disease. Bexarotene has been shown to restore cognitive functions.
Cummings J.L.et al., 2016 To assessethe impact of retinoid X receptor (RXR) agonist bexarotene on brain amyloid in patients with Alzheimer's disease (AD) in a proof-of-concept trial. 20 patients with AD Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease With positive florbetapir scans were randomized to receive 300 mg of bexarotene or placebo for 4 weeks. There was no change in the composite or regional amyloid burden when all patients were included in the analysis. ApoE4 noncarriers showed a significant reduction in brain amyloid on the composite measure in five of six regional measurements. No change in amyloid burden was observed in ApoE4 carriers. There was a significant association between increased serum Aβ1-42 and reductions in brain amyloid in ApoE4 noncarriers (not in carriers). There were significant elevations in serum triglycerides in bexarotene-treated patients. There was no consistent change in any clinical measure. The primary outcome of this trial was negative. Bexarotene reduced brain amyloid and increased serum Aβ1-42 in ApoE4 noncarriers. Elevated triglycerides could represent a cardiovascular risk, and bexarotene should not be administered outside a research setting. RXR agonists warrant further investigations as AD therapies.

Some useful studies characteristics and their expected results.

The below table 2 shows a useful studies and expected results regarding on AD related symptoms. But these studies are not conducted fully with AD patients- it is tested with some kinds of AD related issues. These are case report, a clinical news etc for those we did not included in your study because we can give an information on it but not result of study and claim for proof.


Table 2: Some useful studies characteristics and their expected results.


Study Aim Participant Study design and methods Results Conclusion
Babak Tousi, 2014, United States. To find the Bexarotene for the treatment of cognitive for the treatment of cognitive decline in an individual with Alzheimer’s dementia Female ,79, (breast cancer Andhypertension) with history of memory loss for 10 years, diagnosed with Alzheimer’s dementia 7 years ago. Case report, stopped Aricept and Namenda then was started on Bexarotene 150 mg daily and continued for 3 months. blood tests, liver function test, lipid panel, Blood cell count and thyroid function tests were done at baseline and repeated at week 2, week 6, week 8 and after 3 month treatment and No noticeable change in labs except the gradual increase in cholesterollevel. Omega-3-acid was stared as preventive measure forhypertriglyceridemiaat week 2, Atorvastatin 10 mg for week 6 to treat hypercholestrolemia. Result showed more interactive on week 6 visit, MOCA and ADAS-Cog score did not show any significant change during this period. gradually developed more behavioural symptoms like; sundowning Bexarotene was well tolerated, but did not improve cognition of our patient in moderately severe stage of Alzheimer’s dementia. The patient only developed hypercholesterolemia which responded well to statin therapy. There was worsening of behavioral symptoms which continued after discontinuation of drug, which may be related to the progression of dementia
Johnny Habchi, et al., 2016. UK. To experiment the primary nucleation of Aβ42 and bexarotene with AD. Not stated An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer’s disease. The result are as following:Chemical kinetics-based therapeutic strategies allow to combat Aβ aggregation.- Bexarotene, but not tramiprosate showed delays Aβ42 fibril formation, label-free environment, toxic species in neuroblastoma cells, rescues Aβ42-mediated dysfunction in C. elegans models, restores the motility of C. elegans models of Aβ42-mediated toxicity by preventing Aβ42 aggregation and Bexarotene specifically inhibits the primary nucleation of Aβ42 aggregation. The prevention of the primary nucleation of Aβ42 by compounds such as bexarotene could potentially reduce the risk of onset of Alzheimer’s disease.
Cummings JL, and Kate Zhong, 2013, Cleveland Clinic Lou Ruvo Cente, Braitian. To determine the safety and effect on the brain of the drug bexarotene as a possible treatment for Alzheimer's disease. 20 mild to moderate AD Bexarotene for Alzheimer Disease: Innovative Clinical Trial Could Open the Door to Disease-Modifying. In 2nd trial 300mg for and 1 month (Double Blind Placebo Controlled Randomized Study) to Evaluate the Efficacy and Safety of Bexarotene. Bexarotene can be be applied in new ways for AD Patients. Bexarotene is safety and effect on the brain of the drug bexarotene as a possible treatment for Alzheimer's disease.
Craig T Curtis, 2014. objective of this proof of mechanism pilot clinical trial is to determine if the RXR agonist bexarotene acts in humans to alter the CSF levels of apoE and alter the clearance of Amyloid-Beta Experimental with 12 popilations. age 21-50 years, APOE3/3 genotype A Randomized Controlled Study, AD patients, Bexatorend drugs Experimental: Bexarotene The subjects will be administered three (3) capsules of Targretin™ (75 mg/capsule) on a twice daily basis (450 mg/day) for five days. Placebo Comparator: Placebo.The subjects will be administered three (3) capsules of Avicel PH on a twice daily basis (450 mg/day) for five days. The expected result -Will be effective drug The excepted conclusion-Will be effective drug.
Johannes W. A. Smit et al.,2007. To evaluate the effects of bexarotene on peripheral thyroid hormone metabolism and athyreotic subjects on a fixed substitution dose with L-T4. Ten athyreotic patients with pulmonary metastases of differentiated thyroid carcinoma received 6-wk redifferentiation treatment with 300 mg bexarotene An open prospective 6-week intervention with ten athyreotic patients with pulmonary metastases of differentiated thyroid carcinoma received 6-wk re-differentiation treatment with 300 mg bexarotene/d. L-T4 doses were kept stable. Before and in the sixth week of therapy, serum levels of total T4, free T4 (FT4), T3, reverse T3 (rT3), and TSH were measured. Bexarotene induced profound decreases in total T4 (56% of baseline), FT4 (47%), T3 (69%), rT3 (51%), and T4S (70%) in all patients, where as TSH levels were not affected. The T3/rT3 ratio increased by 43%, and the T4S/FT4 ratio increased by 48%. Serum TSH levels before. In the present study, we demonstrate that increased peripheral degradation of thyroid hormones by a nondeiodinase-mediated pathway contributes to bexarotene induced-hypothyroidism.

Discussion

This is the first systematic review to assess cancer drugs in association with AD. We retrieved many studies representing a huge range of successful cancer treatments mostly focused on hormonal therapy for women with early-stage breast cancer [18,29], impaired cognitive function and hippocampal neurogenesis [30], CNS cancer [31] cognitive impairment, brain structure and risk of dementia [32] cervical cancer, cognitive problem/impairment [33], gastro intestinal in complication, to maintain haemoglobin level, menopausal status [34] and other types of cancers but none specifically with AD. Also, we retrieved a huge range of animal studies- all of which showed future ways ge of animal studies- all of which showed future ways for treating humans with AD [35,36]. However we did not include the animal studies here in this study because our intention was to evaluate cancer therapy for people affected with AD and the possible links between Anti-cancer drugs and AD. Still the questions remain unanswered about the benefits and risk of anti-cancer drugs (Bexarotene’s) when used on patients affected with AD. Also, of interest is how much reduction in Aβ synthesis needs to occur to produce a cognitive benefit?


What is surprising is that only one study examined Bexarotene (chemotherapy group) therapy is known to affect cancer patients and AD patients. However, doxorubicin and cyclophosphamide- for the treatment of chronic lymphocytic leukemia, bladder, breast, head and neck, thyroid, uterus, liver, lung, lymphomas, mesothelioma, ovary, pancreas, prostate, multiple myeloma, neuroblastoma, sarcomas, stomach, testis -germ cell [34], a chemotherapy Imatinib- reduced Aβ-β-amyloid protein/ neuro protective, paxclitaxel treatments of ovarian carcinoma, breast cancer, lung cancer, kaposis’s sarcoma are potential agents in the coming decade. A review study [17] found at least 25-30% of patients with cancer meet also the criteria of a psychiatric condition including depression, anxiety, stress-related syndromes, adjustment disorders, sleep disorders, pain, hot flashes, puritus, nausea and vomiting, fatigue, cognitive impairment and delirium. Psycho-oncology research showed the efficacy of psychotropic drug treatment of cancer-related symptoms. Therefore we may generalize that the vast majority of the above mentioned symptoms frequently appear also in AD patients. That means that treatments for those who have cancer and are using psychotropic drugs might also be beneficial for those who are AD patients.


Likewise, Tropisentron [2 mg (IV) intravenous and 5mg oral] -antagonist used as an antiemetic to treat nausea and vomiting following chemotherapy [37] promoted positive improvement in memory compared to conventional AD therapy, like memantine and donepezil. Some exceptions include- anti diabetics drugs-lixisenatide, exenatide; anti-hypertensive- angiotensin enzyme inhibitors and receptors blocker, hydroclorothiazide, Enalpril, amlodipine, isradipine; anti-viral- acyclovir, penciclovir, foscarnet; anti-microbial- rifampin for microbacterium infection [38], hydroxiclroquine, amphotericin B, erythromycin, tertacyline- minocycline [39]; Glucose disaccharide-threhalose; anti-oxidant (PD)-pramipexol; anti-psychotic- quetiapine, olanzapine, risperidone and anti-asthamic- zileuton [40].


Another dozen medicines are being used with mice (animal models) and are showing significantly improving results in the treatment of AD related data in different study models [13,41-43].


Additionally, there are currently many drugs in the preclinical stages of development, and more than 100 have progressed to human testing 49. Most clinical diagnosis trials of AD agents have not been showing successful results however the cholinesterase inhibitors and memantine showed symptomatic improvement for AD patients In a few cases, unsuitable trials were applied inadequately when testing the trial agent, while with other trials which were suitably applied there was no proof of efficacy [44].


French research revealed [45] that cholesterol and Bexarotene compete for the same bind¬ing site in the C-terminal region of Aβ1-42 which is a protein highly correlated with AD. Bexarotene competed with cholesterol for binding to Aβ and prevented neurotoxic oligomeric formation of Aβ. Likewise, further research showed Bexarotene was able to counteract both Aβ-induced and Aβ-independent increases in cortical net¬work hyper excitability.


A current study [24] on “the emerging role of Bexarotene in the treatment of AD: current evidence” found that Bexarotene, a retinoid X receptor agonist, was shown to reverse neurodegeneration, improve cognition, and decrease levels of amyloid-β in transgenic mice expressing familial AD mutations.


A case report of a woman 79 years old with breast cancer and hypertension and history of memory loss for 10 years, diagnosed with AD 7 years ago of application of Bexarotene 150 mg/d for 3 months. Blood tests, liver function test, lipid panel, blood cell count and thyroid function tests at baseline and repeated at week 2, week 6, week 8 and after 3 months of treatment showed no noticeable change in lab testing and cognition except the gradual increase in cholesterol levels and significant change of behavioural symptoms-sundowning. So we can say Bexarotene was well tolerated [46].


Furthermore, Bexarotene therapy is good for coming drug development in AD treatment, due to its high blood–brain barrier perme¬ability and current safety profile. Bexarotene induced profound decreases in total T4 (56% of baseline), FT4 (47%), T3 (69%), rT3 (51%), and T4S (70%) in all patients, whereas TSH levels were not affected. The T3/rT3 ratio increased by 43%, and the T4S/FT4 ratio increased by 48% [47].


A study has been conducted at the Clevent Clinic, Las Vegas Nevada to determine the safety and effect on the brain of the drug Bexarotene as a possible treatment for AD patients with the min age 50 and max age 90, in both males and females using a double blind placebo controlled randomized study to evaluate the efficacy and safety of Bexarotene in patients with mild to moderate AD. The expected result of that study will come later the mid-year 2015. In the preliminary phase of study patients will receive 300/mg of the anti-cancer drug Bexarotene or a placebo for 1 month and brain scans- hope is that Bexarotene acts to minimise the harmful Aβ protein in the brain; also retinoid X receptors and nuclear receptors will have been connected to numerous metabolic pathways relevant to ΑD and Aβ production and removal [9].


Although there have been many studies on cancer treatments, these have not focused on all forms of active cancer treatment association with AD populations. The strengths of this review include the systematic methodology used to identify all relevant articles from multiple databases and has very few limitations with respect to scientific quality of the studies included. Also, we have not used meta-analysis studies for outcomes. In conclusion, cancer therapy is new approach for the treatment of AD and currently mostly these are in preclinical studies and early phases of clinical trials. With this study we learn more detail about the chemotherapy and disease progression of AD symptoms and an insight into the potential therapeutic evidences. Despite the fact that the bulk knowledge on regarding this chronological disease, only a handful recourse are available for its treatment. The presently applied drugs, Acetylcholinesterase and Buturylocholinesterase Inhibitors for the treatment unfortunately target symptoms only and not the cause of the disease. The hope was significant for AD treatments [5] because chemotherapy drugs are successful at treating cutaneous T-cell lymphomas, cognitive impairment and has been shown to have benefits in mouse models of AD. For the human clinical trials it is still extremely premature to expect effective treatment for AD because of recent warnings for Bexarotene [48,49].


Conclusion

This conclusion presents the strong witness from animal models. However, the perfect model would be on human model studies for the prescription to the AD patient’s because animal model is not sufficient to meet all of the clinical criteria. We found a study that was observed combination of molecular, physicochemical, and cellular approach to examine the mechanisms of underlying the anti-Alzheimer properties of Bexarotene in neural cells and Bexarotene was showed to restore cognitive functions. Obviously, we cannot do refer 100 percent to the AD patients due the very limited human model result. But we can claim that this drugs is a reliable for AD patients because there is no doubt in animal model to reduce the Cholesterol, cognitive impairment and amyloid beta that is a key cofactor of Alzheimer’s disease. Also, female survivors of breast cancer have a lower risk of Alzheimer’s disease (AD) [50]. Thus Cancer Drugs are not a miracle cure for AD- dozens of questions have been raised, however, Bexarotene (chemotherapy) improves cognition and other symptoms that appear with AD patients and will be a significant drug in the coming decades [51-53].


Conflicts of Interest

None.


Funding

No financial support for the research, authorship and publication.

References

  1. DePinho RA (2000) The age of cancer. Nature 408: 248-254. [crossref]
  2. World Cancer Report 2014.
  3. Ganguli M (2015) Cancer and Dementia: It's Complicated. Alzheimer Dis Assoc Disord.
  4. Kemsley T (2013) Anti-Cancer Drug Reverses Memory Loss Due to Alzheimer's in Mice.
  5. Cummings JL, Morstorf T, Zhong K (2014) Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 6: 37.
  6. Vellas B, Hampel H, Rougé-Bugat ME, Grundman M, Andrieu S, et al. (2012) Alzheimer's disease therapeutic trials: EU/US Task Force report on recruitment, retention, and methodology. J Nutr Health Aging 16: 339-345. [crossref]
  7. Martin E, Morel V, Joly D, Villatte C, Delage N, et al. (2015) Rationale and design of a randomized double-blind clinical trial in breast cancer: Dextromethorphan in chemotherapy-induced peripheral neuropathy Contemp Clin Trials 41C: 146-151.
  8. American chemical society 2014. Toward an oral therapy for treating Alzheimer’s disease: using a cancer drug.” Sciencedaily.
  9. Commings JL, Hicson S J (2014) Bexarotene Amyloid Treatment for Alzheimer's Disease (BEAT-AD).
  10. Fitzgerald K (2013) Anti-Cancer Drug Reverses Alzheimer's disease. Medical news today.
  11. Christine Hsu (2012) Claim that Skin Cancer Drug Treats Late-Stage Dementia in Mice.
  12. Jeffrey Kopman (2013) Cancer Drug Not a Miracle Cure for Alzheimer's Disease. Ethan A. Huff 2013. Miracle' Alzheimer's drug bexarotene turns out to be a hoax Learnmore.
  13. Thomson Helen (2012) Cancer drugs reserves Alzheimer’s in mice. Science.
  14. LaFerla FM (2012) Preclinical success against Alzheimer's disease with an old drug. N Engl J Med 367: 570-572. [crossref]
  15. Sharon Parmet (2014) Drugs’s effect on AD may depend on severity of disease.
  16. Ricard D, Taillia H, Renard JL (2009) Brain damage from anticancer treatments in adults. Curr Opin Oncol 21: 559-565. [crossref]
  17. Luigi Grassi, Rosangela Caruso, Karen Hammelef, Maria Giulia Nanni, Michelle Riba, et al. (2014) Efficacy and safety of pharmacotherapy in cancer-related psychiatric disorders across the trajectory of cancer care: A review. Int Rev Psychiatry 26: 44-62.
  18. Goss PE, Ingle JN, Alés-Martínez JE, Cheung AM, Chlebowski RT, et al. (2011) Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 364: 2381-2391. [crossref]
  19. Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, et al. (2012) ApoE-directed therapeutics rapidly clear ß-amyloid and reverse deficits in AD mouse models. Science 335:1503-1506.
  20. Driver JA, Beiser A, Au R, Kreger BE, Splansky GL, et al. (2012) Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study. BMJ 344: e1442. [crossref]
  21. Lange M, Rigal O, Clarisse B, Giffard B, Sevin E, et al. (2014) Cognitive dysfunctions in elderly cancer patients: A new challenge for oncologists Cancer Treatment Reviews 40: 810-817.
  22. Heck JE, Albert SM, Franco R, Gorin SS (2008) Patterns of dementia diagnosis in surveillance, epidemiology, and end results breast cancer survivors who use chemotherapy. J Am Geriatr Soc 56: 1687-1692. [crossref]
  23. Katherine D LaClair, Kebreten F Manaye, Dexter L Lee, Joanne S Allard, Alena V Savonenko, et al. (2013) Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutantAPP/PS1 mice. Molecular Neurodegeneration 8: 26.
  24. Tousi B (2015) The emerging role of bexarotene in the treatment of Alzheimer's disease: current evidence. Neuropsychiatr Dis Treat 11: 311-315. [crossref]
  25. Best A, Greenhalgh T, Lewis S, Saul JE, Carroll S, et al. (2012) Large System Transformation in Healthcare: A Realist Review. The Milbank Quarterly 90: 421-456.
  26. Pawson R. Evidence-Based policy: A realist perspective. London, Sage 2006.
  27. Kosmas Zekynthons. Revolution! Found neo farmako against Alzheimer’s disease? Science Advances. 16_02-2016 in Featured.
  28. Cummings JL, Zhong K, Kinney JW, Heaney C Moll-Tudla J Joshi A, Pontecorvo M, et al. (2016) Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease. Alzheimers Res Ther 8: 4.
  29. Chia YH, Ellis MJ, Ma CX (2010) Neoadjuvant endocrine therapy in primary breast cancer: indications and use as a research tool. British Journal of Cancer 103: 759-764.
  30. Christie LA, Acharya MM, Parihar VK, Nguyen A, Martirosian V, et al. (2012) Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy. Clinical Cancer Research 18: 1954e1965.
  31. Ogawa A (2014) [Cancer treatment for patients with dementia]. Gan To Kagaku Ryoho 41: 1051-1056. [crossref]
  32. Vincent Koppelmans, Monique MB Breteler a,c,d, Willem Boogerd e, Caroline Seynaeve f , Sanne B, et al. (2013) Schagen Late effects of adjuvant chemotherapy for adult onset non-CNS cancer; cognitive impairment, brain structure and risk of dementia. Critical Reviews in Oncology/Hematology 88: 87-101.
  33. Diane Von Ah, Barbara Habermann, Janet S Carpenter, Brandy L Schneider (2013) Impact of perceived cognitive impairment in breast cancer survivors. European Journal of Oncology Nursing 17: 236-241.
  34. Catherine E Jansen, Marylin J Dodd, Christine A Miaskowski, Glenna A Dowling, Joel Kramen, et al. (2008) Preliminary results of a longitudinal study of changes in cognitive function in breast cancer patients undergoing chemotherapy with doxorubicin and cyclophosphamide. Psycho-Oncology 17: 1342.
  35. Jonathan J Sabbagh, Jefferson W Kinney, Jeffrey L Cummings (2013) Animal systems in the development of treatments for Alzheimer’s disease: challenges, methods, and implications. Neurobiology of Aging 34: 169-183.
  36. Selkoe DJ, Bell DS, Podlisny MB, Price DL, Cork LC (1987) Conservation of brain amyloid proteins in aged mammals and humans with Alzheimer's disease. Science 235: 873-877. [crossref]
  37. Hashimoto K (2015) Tropisetron and its targets in Alzheimer's disease Expert Opinion on Therapeutic Targets; informa health care. 19: 1-5.
  38. Tomlyama T, Shoji A, Kataoka K, Suwa Y, Asano S, et al. (1996) Inhibition of amyloid beta protection aggregation and neurotoxicity by rifampicin. Its possible function as a hydroxyl radical scavenger. J boil chem 271: 6839-6844.
  39. Hashimoto K (2011) Can minocycline prevent the onset of Alzheimer's disease? Ann Neurol 69: 739. [crossref]
  40. Brian S (2013) Appleby Dimitrios Nacopoulos Nicholas Milano Kate Zhong Jeffrey L. Cummings. A Review: Treatment of Alzheimer’s disease Discovered in Repurposed Agents. Dement Geriatr Cogn Disord 35: 1-22.
  41. Millington C, Sonego S, Karunaweera N, Rangel A, Aldrich-Wright JR, et al. (2014) Chronic neuroinflammation in Alzheimer's disease: new perspectives on animal models and promising candidate drugs. Biomed Res Int 2014: 309129.
  42. Dementia today (2013) Anti-cancer drug reserves Alzheimer’s disease in mice. Daily news and views on AD and others dementia.
  43. Bomben V, Holth J, Reed J, Cramer P, Landreth G, et al. (2014) Bexarotene reduces network excitability in models of Alzheimer's disease and epilepsy. Neurobiol Aging 35: 2091-2095. [crossref]
  44. Cummings J (2010) What can be inferred from the interruption of the semagacestat trial for treatment of Alzheimer's disease? Biol Psychiatry 68: 876-878. [crossref]
  45. Fantini J, Di Scala C, Yahi N, Troadec JD, Sadelli K, et al. (2014) Bexarotene blocks calcium-permeable ion channels formed by neurotoxic Alzheimer's ß-amyloid peptides. ACS Chem Neurosci 5: 216-224. [crossref]
  46. Babak Tousi (2013) Bexarotene for the treatment of cognitive decline in an individual with alzheimer’s dementia. Cleveland Clinic 9: 301.
  47. Johannes WA Smit, Marcel PM Stokkel, Alberto M Pereira, Johannes A Romijn, Theo J Visser, et al. (2006) Bexarotene-Induced Hypothyroidism: Bexarotene Stimulates the Peripheral Metabolism of Thyroid Hormones. The Journal of Clinical Endocrinology & Metabolism 92: 2496-2499.
  48. Justin Lowenthal, Sara Chandros Hull, Steven D Pearson (2012) The Ethics of Early Evidence-preparing for a Possible Breakthrough in Alzheimer’s disease. N Engl J Med 367: 488-490.
  49. Gandy S, DeKosky ST (2013) Toward the treatment and prevention of Alzheimer's disease: rational strategies and recent progress. Annu Rev Med 64: 367-383. [crossref]
  50. Jean Louis Kraus (2013) therapeutic link betwwen alzheimer’s disease and brain cancer: drug discovery consequences. ChemMedChem 8: 689-692.
  51. Aicardi G (2013) New hope from an old drug: fighting alzheimer’s disease with cancer drug bexarotene(targretin)? Rejuvenation Res 16: 524-528.
  52. Van Dam D, De Deyn PP (2011) Animal models in the drug discovery pipeline for Alzheimer's disease. Br J Pharmacol 164: 1285-1300. [crossref]
  53. Habchi J, Arosio P, Perni M, Costa AR, Yagi-Utsumi M, et al. (2016) An anticancer drug suppresses the primary nucleation reaction that initiates the production of the toxic Aβ42 aggregates linked with Alzheimer's disease. Sci Adv 2: e1501244. [crossref]