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Rapamycin

Posted by Chris on August 22nd, 2013  ⟩  0 comments

Autophagy is a very complicated process when it comes to cancer. In general, autophagy isn’t complicated at all. It is a highly conserved process in which damaged or long-lived proteins and organelles can be removed from cells. Functioning through lysosomal machinery, this process ensures cellular survival during starvation by maintaining cellular energy levels. Think of it as a waste removal/renewable energy source system; bad or unnecessary stuff gets broken down in order to sustain the rest of the cell. This happens in nearly all cells and it works wonderfully.

In cancer, however, the role of autophagy is a bit murkier. Sometimes, autophagy is working with the doctors in the suppression of tumor cells; isolating damaged organelles, allowing cell differentiation or promoting cell death of the cancerous cells. But other times, autophagy is working against the doctors; allowing stressed tumor cells to undergo dormancy and resistance to chemotherapeutic drugs. Such a dichotomy in roles can be very frustrating to the doctors and ultimately deadly to a patient if the therapy is compromised due to the lack of effective autophagy or if the cancer comes back due to effective autophagy. Knowing which cancers use autophagy for survival and which cancers are susceptible to autophagy is key to corrective treatment.

None of this is particularly new, however. The role of autophagy in cancer cells is quite known (there is a dedicated Autophagy Journal, after all). There are also a number of clinical studies on various cancer types which are looking into the use of anti-autophagy drugs in conjunction with chemotherapy drugs. Autophagy-inhibitory drugs can come in one of two types: there are the early-stage inhibitors which can target class III P13K and interfere with its membrane recruitment, and late-stage inhibitors (such as chloroquine, hydrochloroquine and monensin) which prevent the acidification of lysosomes (Yang, 2011). Below is a table of various ongoing (c. 2011) clinical trials utilizing some of these late-stage, autophagy inhibitors.

Autophagy Clinical trials

More recently, a group in South Korea headed by Cheol Hyeon Kim investigated the effect of monensin on two anticancer drugs (erlotinib and rapamycin) in the treatment of lung cancer cells. Erlotinib is an Epidermal Growth Factor Receptor (EGFR) inhibitor which binds to the ATP binding site on the EGFR, which prevents the formation of an EGFR homodimer and its ensuing signaling cascade. Autophagy pathwayRapamycin is a macrocyclic triene, antibacterial drug which also has immunosuppressant and anticancer activities. The major target of rapamycin in mammalian cells is the mTOR pathway, which is a major regulator of autophagy, and which is downstream of the P13K-AKT pathway.

Kim’s group saw an increase in apoptosis in the cells treated with both the anticancer drug as well as nanomolar concentrations of monensin, with a 40% reduction in cells compared to the control and around ~20% reduction compared to the anticancer drug alone (P <0.01). Perhaps this isn’t really that surprisingly, after all. Hydrochloroquine in conjunction with erlotinib is already in a phase 2 trials for lung cancer (see table above). But their published record further assists in the elucidation of how autophagy functions in the realm of cancer cell tumorigenesis and ultimately, that is most important thing right now.

 
 

Choi, H. S., Jeong, E. H., Lee, T. G., Kim, S. Y., Kim, H. R., & Kim, C. H. (2013). Autophagy Inhibition with Monensin Enhances Cell Cycle Arrest and Apoptosis Induced by mTOR or Epidermal Growth Factor Receptor Inhibitors in Lung Cancer Cells. Tuberculosis and Respiratory Diseases, 75(1), 9-17.

Yang, Z. J., Chee, C. E., Huang, S., & Sinicrope, F. A. (2011). The role of autophagy in cancer: therapeutic implications. Molecular cancer therapeutics, 10(9), 1533-1541.

Category Code: 88221 88241

Posted by Chris on November 15th, 2012  ⟩  0 comments

Rapamycin (Gold Biotechnology, R-101) is such a remarkable drug!  It’s a macrocyclic triene antibiotic, an immunosuppressant, it has anti-cancer and anti-proliferative properties and, oh, by the way, it may also help increase your life-span.  That’s an awful lot of properties to keep track of for a chemical compound that looks like this:

 Rapamycin

The antibiotic was first discovered in the late 60’s by Dr. Suren Sehgal on the remote Easter Island (called Rapa Nui by its natives) from a soil sample and later isolated from the bacteria, Streptomyces hygroscopicus, in 1972. (The compound does seem to resemble this Moai a little bit.)  Originally tested as an antifungal agent, it was quickly discovered that it had immunosuppressant properties, effectively killing its application as an antifungal.

Almost lost due to sudden loss of research funding, it was rediscovered in the late 1980’s by Wyeth, in which they found an analogue (CCI-779) that was broadly active against a wide range of tumor types!  Even better, its mechanism was so unique, they named its molecular target TOR (Target Of Rapamycin).  The drug then went on the whirlwind, cancer wonder-drug research circuit, received FDA approval in 2007, and is currently a large part of the drug program used for renal cancer.

But the journey of this humble antibiotic from the farthest corner of the planet would take another leap in public attention.  In 2009, David Harrison et al. discovered that Rapamycin significantly increased the life-span of mice!  Of course, there are always some side effects, such as an increased resistance to insulin…and let’s not forget that Rapamycin is still widely used as an immunosuppressant.  But even more recently, there’s the prospect that treatment with Rapamycin may ameliorate age-dependent obesity and age-related cognitive decline!

So let’s tally this up.  Increase life-span? Check!  Weight loss drug? Check!  Improve age-related mental functions? Check!  And “to get all of this and more!”, all we have to do is live in a bubble without any sugar?  Well…maybe.  Earlier this year, Dudley Lamming et al. was able to uncouple the longevity and insulin resistance effects of Rapamycin, possibly giving us the opportunity to have our sugar-laden cake and eat it too!  Of course, we’ll still be living in that bubble.

But I’m certain within another year or so, some scientist will uncouple that problem as well and we’ll all get to live healthy, double-century lives (or at least those of us with good drug coverage).  As always in science, the possibilities are endless…

1. Garber, Ken. "Rapamycin’s resurrection: a new way to target the cancer cell cycle." Journal of the National Cancer Institute 93.20 (2001): 1517-1519.

2. Yong, Ed. “The two faces of rapamycin – why a life-extending drug also increases risk of diabetes.” Not Exactly Rocket Science-Blogs @ Discover Magazine. 30 March, 2012.

3. Harrison, David E., et al. "Rapamycin fed late in life extends lifespan in genetically heterogeneous mice." nature 460.7253 (2009): 392-395.

4. Di Paolo, Salvatore, et al. "Chronic inhibition of mammalian target of rapamycin signaling downregulates insulin receptor substrates 1 and 2 and AKT activation: A crossroad between cancer and diabetes?." Journal of the American Society of Nephrology 17.8 (2006): 2236-2244.

5. Houde, Vanessa P., et al. "Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue." Diabetes 59.6 (2010): 1338-1348.

6. Yang, Shi-Bing, et al. "Rapamycin Ameliorates Age-Dependent Obesity Associated with Increased mTOR Signaling in Hypothalamic POMC Neurons." Neuron 75.3 (2012): 425-436.

7. Majumder, Smita, et al. "Lifelong rapamycin administration ameliorates age‐dependent cognitive deficits by reducing IL‐1β and enhancing NMDA signaling." Aging cell (2012).

8. Lamming, Dudley W., et al. "Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity." Science Signaling 335.6076 (2012): 1638.

Category Code: 88251 88221