You haven't mentioned the type of cancer that you will be targeting for your project. Every cancer cell is unique in morphology and molecular mechanism with varied response to the drugs. Moreover, even extrinsic apoptotic pathways activate a caspase cascade inside the cell which may have different mechanisms. Epigenetic modulation and chromatin remodeling and intercalating agents are being studied widely which might be promising (You can have a literature search on that). Surprisingly, BCL-2 antagonists - which drive the intrinsic pathway - are beginning to bear clinical fruit. In contrast, clinical attempts to stimulate the extrinsic pathway with proapoptotic receptor agonists (PARAs) have been disappointing, despite compelling preclinical efficacy with this class of agents.

Article Targeting the extrinsic apoptotic pathway in cancer: Lessons...

I am afraid that if you are looking for some chemical substance to destroy the cancer cell without getting into the cell your search will probably be fruitless.

On the other hand you may use physical methods that would do the trick without "entering" the cell (actualy they "enter" the cell on a physical basis). In this case you have resources like radiotherapy or radiofrequency. Other mechanism is starving the cancer cell. You do not introduce any chemical into it, but you do not feed it. At the begining you will find autophagy and finally apoptosis.

Another mechanism that hampers tumor cell's development is alcalinizing the environmenth proton pump inhibitors associated with inhibitors of the carbonic anhydrase and NHE-1 inhibitors like cariporide. All this substances act on the surface of the cancer cell. Their intracellular effect is secondary to their function on the cell membrane.

Asparaginase is used in chemotherapeutic regimens for the treatment of acute lymphoblastic leukemia (ALL). Since ALL cells are deficient in asparagine synthetase, they cannot produce asparagine de novo and depend on its extracellular sources to support protein synthesis and cell growth. Asparaginase depletes serum asparagine, which leads to the apoptosis of leukemic cells (without asparaginase entering leukemic cells).

Hi Tomas,

Thanks for sharing! I checked a bit literature and I guess you mean if we could target NH1 on cancer cell membrane then we could break down the PH control system so as to kill the cancer cells. Did I take it wrong?

Hi Syed,

Yep, sorry about this. Coz I am seeking some generic ways that could inspire me a bit. That's why I didn't mention any specific cell type. I definitely agree with your idea about the interdependence between extrinsic and intrinsic factors. I am actually seeking something special that could initiate apoptosis/ necrosis outside the cells at the beginning, or using special materials' design to physically "slice" the membrane without materials being internalised intracellularly. That seems more tempting to me.

Hi Roman,

Your post is very helpful! I just want to know whether Asparaginase is specifically effective to only leukemic cells?

Yes. That is the point. If you inhibit the proton export mechanisms on the cell membrane like NHE1 and carbonic anhydrase plus voltage gated sodium channels you will create an acid stress at the intracellular level that will lead towards apoptosis .

This is beyond a theory. We have experimental evidence that backs this idea.

You might also try looking at any antibody therapy - these predominantly bind to receptors on the outside of the cells to cause the cells to stop growing, apoptose, or whatnot. A specific variety are the immune blockade inhibitors (anti-CTLA4, anti-PD1/PDL1) which in some cases cause the immune system to activate and attack the cancer. Another example is bevacizumab, which prevents vascularization.

Of course, many of these are in the clinic right now - they're the opposite of novel. Novel suggests a new target which, honestly, I doubt anybody is going to tell you the brand-new target they're working on so you can scoop them.

Decades ago, L-asparaginase has been found to be largely inefficient against solid tumors, besides occasional responses noticed in melanomas and some lymphomas. Now we know that it may be effective against subsets of solid tumors with low level of asparagine synthetase (ASNS), such as, e.g., low-ASNS subsets of ovarian cancers. However, it has not yet been developed for the treatment of solid tumors.

Thanks William,

Just curious, these antibodies are specific to cancer tribes? or they might generate side-effect to healthy cells?

The CTLA-4 and PD-1 antibodies actually bind to T-cells, and cover the receptors that downregulate their proliferation - this essentially hyperactivates them, and auto-immune problems are one side effect. PD-L1 or bevacizumab bind to cancer, but yes - other cells may well express the appropriate ligand, so you could imagine problems there too. Same with any antibody really - there's nothing truly unique about cancer, other than how much of any given molecule it expresses. Anything on the outside of a cancer cell is going to be on the outside of some other cell in the body somewhere.