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MessageSujet: Re: chloroquine   Lun 11 Aoû 2014 - 15:50

The anti-cancer effect of the antimalarial agent chloroquine when combined with conventional chemotherapy has been well documented in experimental animal models. To date, it was assumed that chloroquine increases the sensitivity of cancer cells to chemotherapy by means of a direct effect on the cancer cells. However, a recent study by investigators at VIB and KU Leuven has demonstrated that chloroquine also normalizes the abnormal blood vessels in tumors. This blood vessel normalization results in an increased barrier function on the one hand -- thereby blocking cancer cell dissemination and metastasis- and in enhanced tumor perfusion on the other hand, which increases the response of the tumor to chemotherapy.

Chloroquine is a well-known medicine with a good safety profile that has been in use since World War 2 for the treatment of malaria and certain auto-immune diseases, including rheumatoid arthritis. More recently, chloroquine has also been used in anti-cancer treatment. Chloroquine blocks autophagy, a process that cancer cells use to survive to anti-cancer treatments. Therefore, blocking autophagy would reduce the resistance of the cancer cells to chemotherapy.

Normalization of abnormal tumor blood vessels

Hannelore Maes from the team of Patrizia Agostinis (KU Leuven), together with Anna Kuchnio from the team of Peter Carmeliet (VIB-KU Leuven) have started a study to explain how chloroquine can strengthen the effect of anti-cancer treatments.

"Although it is assumed that chloroquine strengthens anti-cancer treatment by blocking autophagy, there is little in vivo evidence that this is the only way in which chloroquine works. In this study, we found that chloroquine not only has an effect on the growth of the cancer cells, but also makes the tumor environment less aggressive by normalizing the abnormal blood vessels in the tumor," says Patrizia Agostinis.

Peter Carmeliet: "Blood vessel normalization results in improved tumor perfusion. This reduces the aggressive nature of the cancer cells and means that the anti-cancer medicines are better able to reach the cancer cells, which makes chemotherapy more effective. In addition, tumor blood vessel normalization also increases the barrier function of the blood vessels, which reduces the access of cancer cells to the circulation -- the most important transport system for the spreading of cancer cells to other tissues. Therefore, chloroquine can nip the metastatic spreading of cancer cells in the bud, which is the most important therapeutic goal in any tumor treatment."

Disadvantages do not outweigh the benefits -- the impact of this study on the use of chloroquine in anti-cancer treatment

This study forms a new rationale for the use of chloroquine in anti-cancer treatment. With a view to clinical studies (tests on humans) it is important to note that the effects on the tumor vasculature were even observed at chloroquine concentrations that had little effect on autophagy in the cancer cells. This sheds new light on the therapeutic schedule for combination therapy with chloroquine, which could result in decreased toxicity. In other words, the same "old" medicine simultaneously targets the cancer cells themselves and the blood vessels with great efficiency.

---


L'effet anti-cancer de la chloroquine en combinaison avec la chimiothérapie conventionnelle a été bien documentée dans des modèles animaux expérimentaux. A ce jour, il a été supposé que la chloroquine augmente la sensibilité des cellules cancéreuses à la chimiothérapie par l'intermédiaire d'un effet direct sur les cellules cancéreuses. Toutefois, une étude récente menée par des chercheurs a démontré que la chloroquine normalise également les vaisseaux sanguins anormaux dans les tumeurs. La normalisation de ces vaisseaux sanguins résulte en une fonction de bloquage accru, d'une part - cela diminue la diffusion de cellules de cancer et la métastasisation - et en perfusion tumorale accrue, d'autre part, ce qui augmente la réponse de la tumeur à la chimiothérapie.

La chloroquine est un médicament bien connu avec un bon profil de sécurité qui a été en usage depuis la Seconde Guerre mondiale pour le traitement du paludisme et certaines maladies auto-immunes, comme la polyarthrite rhumatoïde. Plus récemment, la chloroquine a également été utilisé dans le traitement anti-cancer. La chloroquine bloque l'autophagie, un processus que les cellules cancéreuses utilisent pour survivre aux traitements anti-cancéreux. Par conséquent, le blocage de l'autophagy permettrait de réduire la résistance des cellules cancéreuses à la chimiothérapie.

La normalisation des vaisseaux sanguins de la tumeur.

Des chercheurs ont entrepris une étude pour expliquer comment la chloroquine peut renforcer l'effet des traitements anti-cancéreux.

"Bien que l'on suppose que la chloroquine renforce le traitement anti-cancer par inhibition de l'autophagie, il y a peu de preuve in vivo que c'est la seule façon dont fonctionne la chloroquine. Dans cette étude, nous avons constaté que la chloroquine n'a pas seulement un effet sur la croissance de les cellules cancéreuses, mais fait aussi rend l'environnement de la tumeur moins agressive en normalisant les vaisseaux sanguins anormaux dans la tumeur », explique Patrizia Agostinis.

"La normalisation des vaisseaux sanguins dans l'amélioration de la perfusion réduit l'agressivité des cellules cancéreuses et signifie que les médicaments anti-cancer sont mieux en mesure d'atteindre les cellules cancéreuses, ce qui rend la chimiothérapie plus efficace En outre, la normalisation de l'arrivée de sang dans la tumeur augmente également la fonction de barrière des vaisseaux sanguins, ce qui réduit l'accès des cellules de cancer de la circulation -. système de transport le plus important pour la propagation des cellules cancéreuses à d'autres tissus, la chloroquine peut tuer la dissémination métastatique des cellules cancéreuses dans l'oeuf, ce qui est l'objectif thérapeutique la plus importante dans un traitement de la tumeur ".

Les inconvénients ne l'emportent pas sur les avantages selon cette étude sur l'utilisation de la chloroquine dans le traitement anti-cancer

Cette étude constitue une nouvelle justification de l'utilisation de la chloroquine à un traitement anti-cancer. En vue d'études cliniques (essais sur les humains), il est important de noter que les effets sur le système vasculaire de la tumeur ont même été observés à des concentrations de chloroquine qui avaient peu d'effet sur l'autophagie dans les cellules cancéreuses. Cela jette une lumière nouvelle sur le calendrier thérapeutique pour la thérapie de combinaison avec la chloroquine, ce qui pourrait entraîner une toxicité réduite. En d'autres termes, le même vieux médicament vise à la fois les cellules cancéreuses elles-mêmes et les vaisseaux sanguins avec une grande efficacité.


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MessageSujet: Re: chloroquine   Jeu 1 Nov 2012 - 15:45

A malarial drug is showing promise in stopping breast cancer before it starts, Mason researchers are discovering during a clinical trial.

Un médiament contre la malaria montre des promesses d'arrêter le cancer du avant qu'il ne commence.

"The bold long-term goal is a short-term oral treatment that prevents breast cancer by killing the precursor cells that initiate breast cancer," says Lance Liotta, co-director of Mason's Center for Applied Proteomics and Molecular Medicine (CAPMM). "And it's looking hopeful."

The PINC trial (Preventing Invasive Neoplasia with Chloroquine) targets ductal carcinoma in situ, or DCIS, the most common type of pre-invasive breast cancer. Chloroquine is a drug given to prevent or treat malaria; it's showing promise in the early phase of the PINC trial.

CAPMM has three ongoing breast cancer research projects, including the PINC trial, which span the full scope of breast cancer's impact on patients.

In the PINC trial, DCIS is the focus. DCIS shows up as white spots in the MRI of a breast. Those white spots are calcifications that may mark the milk ducts where DCIS cells are growing, says Virginia Espina, assistant research professor at CAPMM. Not all DCIS becomes cancer, but all breast cancer goes through the DCIS stage, she says.

If the patient is diagnosed with DCIS after a biopsy, then she can enter the trial, says Espina, adding that the study doesn't interfere with standard medical treatment. Mason researchers are working with Kirsten Edmiston, a breast surgeon at Inova Fairfax Hospital who recruits the patients and clinically directs the trial.

Chloroquine for Every Woman?

De la chloroquine pour chaque femme ?

While patients are waiting between their diagnosis and the surgery, they take chloroquine once a week for four weeks, Espina says.

Pendant que les patientes attendent leur diagnostic et la chirurgie, elle prennent de la chloroquine une fois par semaine pour 4 semaine.

A significant reduction in the lesion's size is the sought-after outcome, says Espina, who can be seen in this video describing individual differences in cancer. The widely prescribed malaria drug chloroquine has few side effects -- a rare rash is one, Espina says. There could come a day when chloroquine is taken by women worldwide to prevent breast cancer.

Une baisse significative de la grosseur des lésions est le résultat tangible. Le médicament contre la malaria, chloroquine, a peu d'effets secondaire. Peut-être qu'un jour toutes les femmes prendront de la chloroquine pour prévenir le cancer du

"We can imagine that in the future every woman will take chloroquine once a year," Espina says. "Chloroquine kills off the pre-malignant cells that are starting to accumulate. You'd do this periodically as a new type of chemo prevention."

La choloroquine tue les cellules pré-cancéreuses qui commencent à s'accumuler. On pourrait prendre la chloroquine une fois/an comme un nouveau type de prévention.

Chloroquine works by stopping autophagy, which is used by cells to survive under stress. "When your cells realize they don't have enough nutrients, they eat themselves," Espina says. "It's a way to make energy when you don't have enough food."

La chloroquine fonctionne en arrêtant l'autophagie qui est utilisée par les cellules pour survivre au stress.

And that's the spot the DCIS cells are in as they pile up in the milk duct. They're not getting enough oxygen and food and are squashed together.

Les cellules pré-cancéreuses s'accumulent dans les conduits pour le lait maternel.

"It's like being in an elevator," Espina says. "You're next to people but not necessarily next to people you know or like. It's the same way for these tumor cells or pre-malignant cells. They're next to a cell, but they're not anchored anywhere, and cells like to be anchored and have a home.

"For all these reasons, they're under stress. When a cell is under stress, it's a life-and-death struggle. They're not just going to die. They're going to do what they can to survive. That's when they use autophagy to stay alive."

Chemotherapy, a common treatment for cancer, can rev up autophagy, Espina says. "A doctor selects a treatment to try to kill the cell, but the cell is trying to survive; it's trying to do what it's programmed to do. We have to find a way to defeat this cellular process."

Chloroquine works like Pepto-Bismol; it alters the cell's digestive process and therefore autophagy. "But the chloroquine doesn't kill the normal cells because the normal cells aren't dependent on autophagy to survive," Espina says.

Individualized Treatment for Metastatic Breast Cancer

The second CAPMM study on breast cancer is funded by the Side-Out Foundation. Researchers are developing individualized treatment for women with metastatic breast cancer. These advanced tumors have spread to other organs, such as the liver, brain and bone, and have limited response to conventional therapies. Standard chemotherapy failed the 25 women Mason has worked with to pinpoint more effective treatments, says Mariaelena Pierobon, CAPMM assistant research professor.

Pierobon is using technology created by Liotta and Emanuel "Chip" Petricoin III to identify which drug targets are activated within each patient tumor. Pierobon's team is building on the promise of personalized medicine by focusing on the molecular profile of the metastatic lesions.

"We hope that by providing physicians with detailed information on the mechanisms that are driving our patients' tumors, we can facilitate the selection of the most appropriate treatment," Pierobon says. "We are trying to guide that decision by using the cutting-edge molecular technologies that were created in our laboratory to select among the FDA-approved drugs that might be the most promising for each patient."

In this approach, patients don't have to wait for new drugs to be developed. "By using drugs that are already approved, you don't have to study toxicity. That's a huge advantage," Pierobon says.

The third study is the I-SPY 2 TRIAL in which CAPMM researcher Julia Wulfkuhle is leading molecular profiling efforts developed uniquely in the Mason laboratory for women with stage II/III breast cancer. The FDA singled out I-SPY 2 as a leading trial design for accelerated drug approval.

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MessageSujet: Re: chloroquine   Mar 5 Avr 2011 - 17:11

Researchers at the University of Pennsylvania School of Medicine may have found a way to turn an adaptive cellular response into a liability for cancer cells. When normal cells are starved for food, they chew up existing proteins and membranes to stay alive. Cancer cells have corrupted that process, called autophagy, using it to survive when they run out of nutrients and to evade death after damage from chemotherapy and other sources. When the Penn investigators treated a group of patients with several different types of advanced cancers with temsirolimus, a molecularly targeted cancer drug that blocks nutrient uptake, plus hydroxychloroquine, an anti-malarial drug that inhibits autophagy, they saw that tumors stopped growing in two-thirds of the patients.

Les chercheurs de l'université de Pensylvanie pourraient bien avoir trouvé un moyen de changer un processus d'adaptation cellulaire en contrainte pour les cellules cancéreuses. Quand les cellules normales manquent de nourriture, elles mâchent les protéines existantes et des bouts de membranes pour rester en vie. Les cellules cancéreuses ont corrompu ce processus, appelé autophagie, en utlisant pour survivre quand elles sont en manque de nutriments pour échapper à la mort après avoir été endommagées par la chimiothérapie et les autres sources. Quand les chercheurs ont traité un groupe de patients aux prises avec différents cancers avec du temsirolimus, un médicament ciblé qui bloque la prise de nutriment par les cellules, et du hydroxychloroquine, un médicament anti-malaria qui inhibe l'autophagie. Ils ont vu ces tumeurs arrêtées pour deux patients sur trois

Amaravadi's team is presenting the data at the American Association for Cancer Research 102nd Annual Meeting 2011 in Orlando on Tuesday, April 5.

"The results are very encouraging -- striking, even" says senior author Ravi Amaravadi, MD, an assistant professor of Medicine at Penn's Abramson Cancer Center. "Temsirolimus by itself has little effect in this patient population. Tumors laugh at it, with response percentages of just zero to 5 percent. But by combining it with hydroxychloroquine, we found that 14 out of 21 patients had stable disease after treatment, including five out of six melanoma patients."

Les résultats sont très encourageants, frappants même, Le temsirolimus par lui-même a peu d'effets pour les patients, les tumeurs se rient de lui, avec une érponse de 0 à 5 % Mais en le combinant avec l'hydroxychloroquine, nous avons trouvé que 14 patients de 21 ont stabilisé leur maladie après le traitement, incluant 5 patients avec un mélanome sur 6

In addition to melanoma, patients involved in the study also had colorectal, head and neck, breast, gastro-esophageal, prostate, pancreatic, lung and adrenal cancers. Not only did patients show substantial rates of disease stabilization with the treatment combination, but the researchers report that side effects observed were relatively limited; most commonly mouth sores, weight loss, nausea, and fatigue. Two patients developed infections when the large tumors they had at the start of the trial caved in on themselves as treatment killed off the internal cancer cells, but both patients responded to antibiotics and were able to remain on the study regimen.

non seulement des patients avec ces etc. ont eu des taux de stabilisation subtanciels mais les chercheurs rapportent peu d'effets secondaires.

Amaravadi's group was able to see evidence of autophagy inhibition in peripheral blood cells in patients treated with the combination. And the inhibition increased with increasing doses of hydroxychloroquine, suggesting that the drug is working as they hypothesized it would.

More serious side effects, including low blood cell counts, in a previous phase I trial that combined hydroxychloroquine with chemotherapy and radiation. "That was unexpected and shows that hydroxychloroquine is an experimental drug, even though it has been approved for other treatments for many years," he says. "We didn't see that problem in this trial, so our findings show that what you combine it with is critical -- and some combinations will be less tolerable."

The researchers note that the relatively limited side effect profile of the novel temsirolimus-hydroxychloroquine combination suggests researchers may be able to layer other therapies on top of it, making the combination an even more powerful treatment.

Given the large proportion of melanoma patients who benefited from this combination in the initial cohort of patients, the investigators are currently enrolling an additional 12 patients in an expansion cohort at the 1200 mg dose of hydroxychloroquine. They are also hopeful that the drug combination will also be useful in patients with head and neck and breast cancers.

Étant donné la grand proportion de patients avec un mélanome qui bénéficie de cette combinaison de médicament dans la cohorte initiale, les chercheurs enrolent 12 patients additionnels. Ils espèrent aussi que la combinaison de médicaments sera utile pour le cancer du cou et de la tête et celui du

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MessageSujet: Re: chloroquine   Jeu 31 Mar 2011 - 14:40

(Mar. 16, 2011) — Dana-Farber Cancer Institute scientists report they have shrunk or slowed the growth of notoriously resistant pancreatic tumors in mice, using a drug routinely prescribed for malaria and rheumatoid arthritis.

Des scientifiques rapportent avoir rétréci ou ralenti la croissance de tumeurs du pancréas notoirement résistantes chez des souris en utlisant un médicamnet prescrit pour la malaria et les rhumaitistes.

The pre-clinical results, which will appear in the April issue of the journal Genes & Development and is currently published on its web site, have already prompted the opening of a small clinical trial in patients with advanced pancreatic cancer, one of the deadliest and hardest-to-treat forms of cancer, said the investigators, led by Alec Kimmelman, MD, PhD, a radiation oncologist at Dana-Farber.

Ces résultats pré-clinique vont être publiés sous peu en avril dans le Journal "Genes et developpement" etmais déja il y a un petit essai clinique sur quelques patients avec le cancer du

"We are seeing robust and impressive responses in pancreatic cancer mouse models," said Kimmelman, whose laboratory specializes in studies of pancreatic cancer, the fourth-leading cause of cancer death in the United States. The oral drug, hydroxychloroquine, is inexpensive, widely available, and causes relatively mild side effects, he said. A second, planned clinical trial will combine the drug with radiation.

Nous avons vu des réponses robustes et impressionnantes sur des modèles de souris a dit Kimmelman. Le médicament oral, hydroxychloroquine est peu cher largement disponible et cause peu d'effets secondaires. Un autres essai clinique sera fait pour combiner le médicament avec de la radiation.

"While these findings are indeed exciting and a cause for optimism, one needs to be mindful that so far the effects, while impressive, have only been shown in mice," said Ronald DePinho, MD, director of the Belfer Institute for Applied Cancer Science at Dana-Farber. "I eagerly await to see how the human studies will progress."

Bien que ces découvertes soient excitantes et fournissent une raison d'être optimiste il faut se rappeler que les résultats ont été vu sur des souris seulement. J'ai hâte de voir comment les études sur les humains progressent.

A new treatment avenue would be extremely welcome in pancreatic cancer. The National Cancer Institute estimates that 43,140 people were diagnosed in 2010 and 36,800 died. Despite some recent gains with targeted molecular agents and combination regimens, only about 6 percent of patients live five years, and the median survival is less than six months.

Un nouveau traitement serait extrêmement bienvenue pour le cancer du

Hydroxychloroquine is a form of the drug chloroquine, which is used to prevent and treat malaria and also prescribed for autoimmune diseases, including lupus and rheumatoid arthritis. These compounds have recently stirred much interest in cancer research, because they inhibit a process called autophagy (from the Greek for "self-eating") that is elevated in cancer cells.

L'hydroxychloroquine est une forme du médicament chloroquine qui est utilisé pour prévenir la malaria (...) Ces molécules ont attiré récemment l'attention pour la recherche dcontre le cancer parce qu'elles inhibent un processu appelés autophagie qui est élevé parmi les cellules cancéreuses.

Autophagy is present in normal cells as well, but at a much lower level. The process enables cells to break down and eliminate proteins, such as damaged cell membranes and worn-out organelles like mitochondria. But it is also a survival strategy. When nutrients are scarce, cells can digest and feed on their own non-critical proteins to avoid starvation.

L'autophagie est présente normalement dans les cellules mais à un niveau moindre. Le processu permet aux cellules de briser et d'éliminer certaine protéines comme des enveloppes de cellules endommagées ou des organelle déchirées comme des mithochondries. Mais c'est aussi une startégie de survie. Quand les nutriments sont moulus, les cellules peuvent les digérer et nourrir leurs propres protéines pourne pas mourir de faim.

Cancer cells also use autophagy to outwit chemotherapy treatment. Research has shown that cancer cells can activate this process in response to a variety of cancer treatments, allowing them to survive during the stress of therapy. But, as Kimmelman noted, autophagy can also be a cell-death mechanism. Cancer researchers are intensely studying -- and debating -- how to manipulate autophagy as a potential method to slow tumors' growth or make them more sensitive to other therapies.

Les cellules cancéreuses peuvent aussi utiliser l'autophagie pour survivre aux traitements chimiothérapiques. La recherche a démontré que les cellules cancéreuses peuvent activés ce mécanisme en réponse à une variété de traitement contre le cancer. Les chercheurs débattent comment manipuler l'autophagie pour ralentir la croissance du cancer ou le rendre plus sensible aux thérapies.

In their research reported in Genes & Development, Kimmelman and colleagues were stunned to find that autophagy was turned on at all times in pancreatic cancer cell lines -- not just under conditions of stress, treatment or starvation. "This was a big surprise," he said. "These cells weren't deprived of nutrients; they were swimming in all the nutrients they could ever want." This suggested that for some unknown reason, pancreas tumors are highly dependent on autophagy, and therefore potentially uniquely good candidates for autophagy-inhibiting treatment.

In their next experiments, the team administered chloroquine to several different pancreatic cancer cell cultures, and also tested its effects in three types of mouse models. In the laboratory cultures, they reported, the drug "markedly decreased" the growth of the tumor cells, showing that the cells were heavily dependent on autophagy to for continued growth.

Dans leur expériences, ils ont administré de la chloroquine à différentes cellules cancéreuses pancréatiques et testé ses effets sur trois sortes de souris modèles. En laboratoire, ils rapportent que le médicament décroit beaucoup la croissance des cellules cancéreuses et cela montre que ces cellules dépendent beaucoup de l'autpphagie pour survivre et continuer à croitre.

In vivo testing involved three types of mouse models -- human pancreatic cancer cells placed under the rodents' skin (xenografts); human cells injected into the animals' pancreases (orthotopic transplants); and a genetic model (mice bioengineered to develop native pancreatic tumors).

The response to chloroquine was "profound" in the xenograft models, Kimmelman said: All eight untreated mice died of their cancer within 140 days, while only one of eight treated mice had died by 180 days.

The drug's effects were less dramatic but still impressive in the orthotopic and genetic mouse models, the researchers said. The tumors that developed in the genetically pancreatic cancer-prone mice were, like their equivalent in human patients, extremely resistant to all treatments. Among other properties, these tumors were embedded in tough, fibrous tissue that is difficult for drugs to penetrate.

Nevertheless, the scientists reported that chloroquine treatment as a single agent increased the rodents' survival by 27 days compared with untreated control mice. This is encouraging, Kimmelman commented, because even the newest targeted drugs aimed at pancreatic cancer "don't have much effect in this genetic mouse model."

The Dana-Farber trial of hydroxychloroquine, led by Kimmelman and oncologist Brian Wolpin, MD, is designed to enroll 36 pancreatic cancer patients in whom first- or second-line treatments have failed. The drug is taken in pill form twice a day. Results won't become available for at least a year, said Kimmelman.

Kimmelman said the next step will be to investigate the combination of hydroxychloroquine with radiation in patients with operable pancreatic cancer.

"This is a very interesting and promising approach, attacking the Achilles' heel in pancreatic cancer's defenses," commented Robert Mayer, MD, of Dana-Farber's Center for Gastrointestinal Oncology. "But it's too early to say whether hydroxychloroquine should be added to chemotherapy, and what the risks and benefits might be, so we want to examine it in a clinical trial."

Kimmelman's lab is also investigating other forms of cancer that might be good candidates for inhibition of autophagy by the drug. He said that their work, as well as recent findings from other labs, suggests that those cancers may be ones that are primarily driven by the KRAS oncogene -- as nearly all pancreatic tumors are.
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MessageSujet: Re: chloroquine   Lun 16 Nov 2009 - 17:32

Nov. 16, 2009— A powerful new breast cancer treatment could result from packaging one of the newer drugs that inhibits cancer's hallmark wild growth with another that blocks a primordial survival technique in which the cancer cell eats part of itself, researchers say.
Un puissant nouveau traitement pourrait résulter du fait d'envelopper un des plus récents médicaments qui inhibe la croissance sauvage du cancer avec un autre médicament qui bloque un de ses moyens de survie dans lequel les cellules cancéreuses mangent une partie d'elles-mêmes.
While they are powerful killers of some breast cancer cells, new drugs called histone deacetylase inhibitors, or HDAC inhibitors, also increase self-digestion, or autophagy, in surviving, mega-stressed cells, Medical College of Georgia Cancer Center researchers reported during the Molecular Targets and Cancer Therapeutics International Conference in Boston. The conference is sponsored by the American Association for Cancer Research, the National Cancer Institute and the European Organisation for Research and Treatment of Cancer.
Même si elles sont de puissants tueurs de cellules cancéreuses su , les nouveaux médicaments appelés inhibiteurs d'histone deacetyle, ou inhibiteurs HDAC, augmentent l'autophagie en laissant survivre ainsi les cellules très stressées.
"To meet the energy demands of growth and survival, cancer cells start eating up their own organelles, so that surviving cells become dependent on this autophagy," says Dr. Kapil Bhalla, director of the MCG Cancer Center.
"Pour rencontrer les demandes d'énergie de croissance et de survie, les cellules cancéreuses commencent à manger leur propres organelles ainsi les cellules survivantes deviennent dépendantes de leur autophagie" dit le docteur Bhalla.
"By also using autophagy inhibitors, we pull the rug out from under them. The only way out is death," he says.
"En utilisant également des inhibiteurs d'autophagie,nous leurs tirons le tapis sous les pieds. Le seul chemin qui leur restent est de mourir."
Researchers showed the potent HDAC inhibitor panobinostat's impact on autophagy in human breast cancer cells in culture as well as those growing in the mammary fat pads of mice. When they added the anti-malaria drug chloroquine, which inhibits autophagy, breast cancer kill rates increased dramatically.
Les chercheurs ont démontré que le puissant inhibiteur HDAC panobinostat a un impact sur l'autophagie dans les cellules du cancer du humain en culture aussi bien que sur les souris. Quand les chercheurs ajoutent de la chloroquine, un médicament anti-malaria qui inhibe l'autophagie, le taux de mort des cellules cancéreuses augmente de beaucoup.

"As breast cancer is growing, it's developing these mechanisms of resistance to death," says Dr. Bhalla, Cecil F. Whitaker, Jr., M.D./Georgia Research Alliance Eminent Scholar in Cancer and Georgia Cancer Coalition Distinguished Cancer Scholar. "What we are saying is there is a new way to affect a resistant population."
Fundamentals of survival and growth put a lot of stress on cancer cells. Their drive for both comes from the activation of oncogenes and loss of tumor suppressor genes that leaves cells looking desperately for ways to support their marching orders. Much like the extreme measures plane crash victims may take while stranded on a frozen mountaintop, autophagy becomes a survival strategy for the most stressed out cancer cells.

Stress kicks in as cancer cells quickly outgrow available blood supplies and nutrients, which stimulates new blood vessel formation and consumption of unprecedented amounts of fuel. Alterations in gene copy numbers create an imbalance in gene products or proteins adding to the stress of cancer cells, which are starting to make improperly folded -- and functioning -- proteins.

Protein degradation gets revved up and cells also start making more heat shock proteins which are supposed to help properly fold proteins and protect against cell death, a stress cause and effect Dr. Bhalla showed nearly a decade ago. He suspected then the connection he just found: promoting autophagy is one way heat shock proteins carry out their protective mission.
This is where HDAC inhibitors come into play: they promote acetylation or a modification in the key heat shock protein, hsp70, which further promotes autophagy. "Basically HDAC inhibitors promote acetylated hsp70 which promotes autophagy on which a stressed-out cancer cell depends," Dr. Bhalla says.

He notes that chloroquine, a known anti-malarial and inhibitor of autophagy, already is being paired with chemotherapy and radiation is some cancer clinical trials. But because of its significant side effects, new, more tolerable autophagy inhibitors need to be developed which can be combined with currently available anticancer agents, such as panobinostat, to attain superior therapeutic effect against breast cancer, Dr. Bhalla says.
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MessageSujet: chloroquine   Lun 5 Jan 2009 - 14:12

(Jan. 5, 2009) — A single tumor-suppressing gene is a key to understanding, and perhaps killing, dormant ovarian cancer cells that persist after initial treatment only to reawaken years later, researchers at The University of Texas M. D. Anderson Cancer Center report in the December Journal of Clinical Investigation.

Un simple gène est une clé pour comprendre, et peut-être tuer, les cellules cancéreuses et dormantes de l'ovaire qui persistent après le traitement initial pour se réveiller des années plus tard

The team found that expression of a gene called ARHI acts as a switch for autophagy, or self-cannibalization, in ovarian cancer cells. Often a mechanism for cancer cell death, in this case "self-eating" acts as a survival mechanism for dormant cancer cells.

L'équipe a trouvé que l'expression d'un gène appelé ARHI agit comme une switch pour l'autophagie chez les cellules cancéreuses de l'ovaire. Souvent un mécanisme pour la mort des cellules cancéreuses, dans ce cas-ci l'autaphagie, agit comme un mécanisme de survie pour les cellules dormantes du cancer.

"Prolonged autophagy is lethal to cancer cells, but a little autophagy can help dormant cancer cells survive, possibly by avoiding starvation," said senior author Robert Bast, M.D., vice president for translational research

Une autophagie prolongée est mortelle pour les cellules cancéreuses, mais un peu d'autophagie peut aider les cellules cancéreuses à survivre et possiblement éviter de mourir de faim"

"Dormant cells are a major problem in ovarian cancer, breast cancer and other malignancies," Bast said. "We often see ovarian cancer removed, leaving no remaining sign of disease. After two or three years, the cancer grows back. If any remaining cancer cells had continued to grow normally, the disease should have returned in weeks or months.

"Les cellules dormantes sont un problème majeur dans le cancer de l'ovaire, le cancer du sein et d'autres cancers" dit Bast "Nous voyons souvent des cancers qui sont enlevés et dont ils ne restent aucun signes visible revenir après 2 ou 3 ans. Si une cellule restante avait continué à croitre normalement, la maladie serait revenue dans les semaines ou les mois suivant l'opération."

"So the assumption is that some cells remain dormant without dividing and without developing a blood supply, but the mechanism for this has not been well understood," Bast said.

Bast and colleagues focused on ARHI, short for aplasia Ras homolog member I, a gene found in normal cells, but that is underexpressed in 60-70 percent of ovarian cancers.

When normal levels of ARHI were restored to ovarian cancer cells in the laboratory, autophagy was induced and cancer cells died within a few days.

Quand le niveau normal de ARHI a été restauré dans le cancer ovarien en laboratoire, l'autophagie a été induite et les cellules cancéreuses sont mortes en dedans de quelques jours.

When the experiments moved to human ovarian cancer grafts in mice, a different effect was noted. ARHI stopped tumor growth and induced autophagy, but did not kill the cancer cells. When ARHI was turned off at 4 to 6 weeks, the ovarian cancer cells grew rapidly.

Quand les expérimentateurs ont essayés sur des cancers greffés sur des souris, un effet différent a été noté. L'ARHI a arrêté la croissance de la tumeur et a induit l'autpphagie, mais cela n'a pas tué les cellules cancéreuses. Quand l'ARHI a été neutralisé à 4 ou 6 semaines, les cellules de cancer ovarien ont repris leur croissance rapidement.

"Cancer cells had remained viable during ARHI-induced growth arrest and autophagy, which is consistent with a dormant state," Bast said. "When we blocked autophagy with chloroquine, a drug also used to treat malaria, regrowth of the cancers was inhibited, suggesting that autophagy had helped the cancer cells to survive in the absence of a blood supply."

Les cellules cancéreuses ont demeuré viable durant l'arrêt induit et l'autpphagie, ce qui est consistant avec un état dormant" dit Bast " Quand nous avons bloqué l'autpphagie avec le choroquine, un médicament utilisé aussi pour traité la malaria, la croissance du cancer a été inhibé, suggérant que l'autophagie a aidé les cellules cancéreuses a survivre en l'absence de sang."

Autophagy is a cellular survival mechanism that protects cells in a variety of ways. In the case of stress caused by lack of nutrients, autophagy is roughly comparable to a person burning body fat to survive the absence of food.

Several protein survival factors were detected within the microenvironment of the ovarian cancer grafts that could prevent autophagy-induced death of ovarian cancer cells in the laboratory. Blocking these survival factors could provide a novel strategy for eliminating dormant ovarian cancer cells and curing more patients.

Whether cancer cells die an autophagic death, remain dormant or exit dormancy to grow again depends on the balance between ARHI's tumor-suppressing activity and the anti-autophagic and proliferative activity of these environmental survival factors, the authors note.

The ARHI-autophagy pathway also provides an inducible model for tumor dormancy. Lack of a model has hindered understanding of dormant cells and the development of treatments to eliminate them, Bast noted.

Le chemin cellulaire de l'autophagie de l'ARHI fournit un modèle pour la dormance de la tumeur. Le manque de modèle a empêché la compréhension des cellules dormantes et donc le développement de traitement poure les éliminer a noté Bast.

The research was funded by grants from the National Cancer Institute, the National Foundation for Cancer Research and the Blanton-Davis Ovarian Cancer Research Fund.


Dernière édition par Denis le Lun 11 Aoû 2014 - 15:51, édité 6 fois
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MessageSujet: Re: chloroquine   Aujourd'hui à 22:19

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