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Potent Natural Cocktail using Liposomal Delivery

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(@timmur)
Joined: 2 years ago
Posts: 35
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A cocktail of betulinic acid, parthenolide, honokiol and ginsenoside Rh2 in liposome systems for lung cancer treatment

 

Very effective and not really optimized at all. 


   
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(@j)
Joined: 6 years ago
Posts: 2136
 
Posted by: @timmur

A cocktail of betulinic acid, parthenolide, honokiol and ginsenoside Rh2 in liposome systems for lung cancer treatment

 

Very effective and not really optimized at all. 

It still amazes me why synergies are used so little, and as you mention even suboptimal combinations produce surprising results. The efficacy and favorable toxicity profile of such synergistic treatments can't be denied yet there's so little interest.


   
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(@timmur)
Joined: 2 years ago
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Pleiotropy, Complex Adaptative Systems, and Cancer Therapies: No Silver Bullets

First, what is pleiotropy? Put simply, pleiotropy is the state of having numerous effects.

Literally, pleiotropy means "at more than one turn." In that, every engineer deeply knows the meaning of pleiotropy (although very few actually know it by that name).  What the word means in common terms (to both biologists and engineers) is: "Change one a single item (a gene, a bit of code in a software program, the placement of a mechanical strut) and other subsystems may be affected in wholly unexpected manners."  In politics, the effect is known as "the law of unintended consequences," and that too is the same thing. In genetics, it is used to describe a single gene that controls or influences several (potentially unrelated) phenotypic characteristics. In pharmacology, it’s a characteristic of a medication that causes it to have extra effects in addition to the ones it was designed to have, and those are what we call “side effects”.

Pleiotropy is an inevitable consequence of all complex systems, whether the system be ecological, social, mechanical, or genetic. No complex system exists without extensive pleiotropy – nor can it be designed out of a system, no matter how extensive the effort. The best that can be done is to attempt to minimize its effects, but even in that effort, total success is unachievable.

Refined pharmacological drugs attempt to do just that; they aim to minimize pleiotropy and primarily produce desired effects. Of course, that isn’t achievable, but maximizing on-target effects and limiting off-target effects is the precise goal. This sound laudable, and perhaps it is most of the time, however, this is not necessarily a good thing when we are dealing with something like cancer. Cancer is really life itself, and life is nothing if not adaptable. Evolution ensured multiple fail-safes and redundancies because death is, in the end, a harsh teacher. We can think of life as a complex adaptive system and organisms as instances of complex adaptive systems. As such, we shouldn’t be surprised to find that the part of us that’s run amok is incredibly adaptive to the therapies we develop to combat it. Perhaps too, the view that cancer itself is a nested complex adaptive system within a larger complex adaptive system is the right way to view this?

We also shouldn’t be surprised to learn that therapies that have lots of pleiotropic effects are better than mono therapies or therapies that are overly specific. Natural compounds or substances are generally more pleiotropic than the drugs we design or refine from nature. Consider too that multiple substances will likely have more pleiotropic effects than just single substances. This is generally good news because that broad spectrum of effects (relatively speaking) offers the possibility of additive or even synergistic effects. Keep in mind that it can mean potential antagonism as well.

Tumor Cell Heterogeneity: The Greatest Obstacle to Curative Cancer Therapy

Key Problems

  • how to hit multiple tumor clones?
  • how to hit multiple tumor clones at multiple anatomic sites of metastatic disease?
  • how to hit clones that emerge as escape variants driven by the selection pressure of treatment?
    • intrinsic resistance (exist before treatment)
    • acquired resistance (mutations induced by Rx – similar to antibiotic resistance)

This is where pleiotropy can be our friend. Our only hope is to use substances that have many simultaneous positive effects and have minimal toxicity. That’s not what is done today.

Current Approach

  • Design a single drug that hits multiple clones and multiple signaling pathways
    • this has a very low probability of technical success
    • creating a single molecule with multi-target pharmacological promiscuity and no off-target effects (toxicity) is like winning the lottery
  • Or utilize drugs that aren’t selectively injurious to cancer cells only (or mostly)

That cocktail-type therapies are probably the only meaningful way to improve cancer outcomes should now become obvious based on what we know about the nature of cancer and the need to block as many different pathways simultaneously as possible.  As Johan pointed out, the benefits are obvious and toxicity is lower, so why not? The funny thing is that almost anyone who has been successful at beating cancer already knows all of this. They have likely used multiple modalities and approaches. Ironically, the industry that is supposed to be good at defeating cancer (yet is terrible at it) hasn’t learned this lesson. Why that is, is a story for another day.


   
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