March 29, 2013

Rediscovered: The Achilles Heel of Cancer by $PVCT's Craig Dees

(c. 2007)

The majority of today’s cancer therapies differ little, in principle, from treatments developed during medicine’s pre-scientific days, when the practice of healing was more art than science. Back then, lacking specific therapies for diseases like syphilis or malaria, physicians treated patients with poisons, for example arsenic, in the hope was that the poison would kill the disease faster than it killed the patient. For every apparently miraculous cure ten patients died and perhaps ten times as many became deathly ill without their disease improving.

Quack cures persist to this day. Patients spend tens of thousands of dollars on magnets, potions, and various “remedies” that are as effective as medieval cures like bleeding and arsenic. For instance, cancer patients still travel to Mexico for the apricot-pit cancer “cure” laetrile, which contains high levels of cyanide. Every so often patients taking such remedies are cured because their cancer is poisoned faster than the rest of their body.  These random, rare successes add to the mythology, while the hundreds or thousands of patients who wasted their money or were poisoned to death are quickly forgotten.

The majority of therapeutic regimens for cancer are more refined and more technically complex than laetrile, but at their core they differ from laetrile only in their chemical composition. Cancer patients treated with “cocktails” of cytotoxic agents often do not realize that these drugs are among the most toxic and potent carcinogens known.  It is no surprise that the majority of current cancer treatments have limited efficacy and are associated with multiple, serious side effects – including new cancers – that are observed if the patient lives long enough. 

Interestingly, cyanide, the active ingredient in laetrile, is not listed as a mutagen, carcinogen, or teratogen in the RTECS (Registry of Toxic Effects of Chemical Substances) database whereas the approved anti-cancer agents 5-fluorouracil, vinblastine, adriamycin, ad infinitum are.

The goal of cancer chemotherapy, to kill rapidly-growing cancer cells while sparing healthy tissues and minimizing side effects, has only recently been approximated by the introduction of targeted and “personalized” therapies. Most such drug regimens use a test to determine beforehand if a patient will respond favorably to a chemotherapy agent, or suffer abnormally serious side effects. Unfortunately, these agents offer only modest survival benefit, if any, at significantly higher cost than conventional chemo. The modest improvements conferred by targeted cancer therapies still rely, for the most part, on highly toxic chemotherapeutic effects.

Why does chemotherapy fail? Generally, it is because conventional anti-cancer agents fail to home in on molecular targets that are truly unique to cancer cells. For example, new protein kinase inhibitors work because kinase activity is elevated in, but not unique to, cancer cells. Kinases similar to those targeted by newer chemotherapy drugs are present in normal, healthy cells as well as in tumors. Additionally, cancer cells almost immediately evolve new pathways to bypass the effects of the kinase inhibitor drugs, and thereby become resistant to inhibition by kinase inhibitors.

New scientific discoveries fail to catch on for various reasons. The issue of doubt, that something is too good to be true, is one factor that is usually justified. More often the methodology surrounding a discovery is flawed. For example, scientists frequently extrapolate from tissue culture to living organisms, only to be disappointed when experiments are carried out on living organisms. Every competent cancer researcher knows that results obtained from tissue culture studies should be taken with a (very large) grain of salt. I would personally prefer never to dose another poor test animal, but I realize that in my field progress is only possible through experimentation on living organisms, and ultimately in humans.

The “Achilles heel” of cancer was discovered years ago, but abandoned due to what was believed to be a faulty experimental protocol with no practical application to treating humans.  In 1994, Fossel et al.[i] reported that the peroxidation of very large lipoproteins creates toxic substances that kill cultured cancer cells, but not normal cells growing in the same culture dish. Fossel determined that these peroxidated lipids enter the cell by binding to specific lipoprotein receptors on the cell membrane, from where they are transported to intracellular organelles called lysosomes.

Lysosomes are reservoirs of hydrolytic enzymes that function in a highly acidic environment (about pH 4.0). Release of these enzymes from their lysosome containers is, moreover, part of a normal cell’s self-destruct mechanism. Fossel correctly noted the toxic peroxidated lipoproteins functioned by causing the lysosomes to release their contents, which caused the cancer cells to digest themselves (a process called autophagy).

Unfortunately, these interesting studies demonstrating the Achilles heel of cancer cells never received the attention they deserved. After all, these results were obtained in cultured cells, and peroxidated lipoproteins are impractical as drugs. However, the relevance of lysosomes as a critical target for fighting cancer is now being revisited.

For example, cancer cells are now known to possess much higher activity of lysosomal acid hydrolases. This is not surprising since the cells are replicating at a much higher rate and thus require increased levels of oxygen, fuel and building materials. It is also known that intratumoral acidity differs significantly from that of normal tissue (about pH 6.2 compared to pH 7.2 to 7.4 for normal tissue). The low pH of the intratumoral environment can be easily explained by the increased metabolic activity of the cancer cells. The centers of tumors are frequently necrotic because the blood and oxygen supply cannot keep up with the needs of rapidly replicating tumor cells.  In low oxygen environments cells use alternative metaboloic pathways that create lactic acid, which may contribute to the acidity inside tumors.

Other mechanisms may also contribute to the low pH of tumors. For example, Glunde et al.[ii]  reported that cancer cells secrete lysosomal contents into the extracellular milleu. Ostensibly, one can explain this as a type of parasitic mechanism where the cancer cells attempt to divert resources from neighboring cells though the activity of acid hydrolases. This exocytosis of acidic hydrolases could also contribute to the process of metastasis whereby cancer cells effectively “cut” their way out of the tumor, allowing them to move to a remote site. Dumping of the acidic lysosomal contents outside the cell would also contribute to the low-pH intratumoral environment.

The role of lysosomes in cancer is much better understood than in 1994 when Fossel demonstrated that lysosomes could be selectively recruited to kill tumor cells. While this work provided a glimpse into a vulnerability of cancer cells, peroxidated lipoproteins are only useful as a research tool and impractical as a therapeutic agent.  The very large size of the peroxidated complex makes them difficult to manufacture, sterilize and use to treat patients. Additionally, the best source of lipoproteins would be from human blood, which presents further hurdles of harvesting, purification, and sterilization. Therefore, exploitation of cancer’s Achilles heel only occurred recently, with the discovery that small molecule drugs could achieve the same results as that demonstrated by Fossel, and through a similar mechanism.

Recently, Fehrenbacher and Jaattela[iii] and Hersey et al.[iv] noted that lysosomes could be recruited to kill cancer cells selectively. However, even more convincing was the discovery that the small molecule dye (Rose Bengal, AKA PV-10) could be induced, under the proper conditions, to specifically target cancer cell lysosomes, resulting in the death of cancer cells both in vitro and in vivo. The specificity of PV-10 for tumors is so high that few if any extra-tumor effects are produced.

PV-10 works through lysosome activity that is very similar to that suggested by Fossel’s pioneering work. PV-10 selectively enters diseased cells by a number of routes. For example, in the saline environment of blood, it binds to lipoproteins, which may transport it into cancer cells selectively since many cancers exhibit highly up-regulated lipoprotein receptors. The number and activity of lipoprotein receptors is increased in cancer cells to support the active replication of these cells, which requires a high influx of nutrients and building materials which cells use to divide and grow.

We have demonstrated that PV-10 partitions from saline environments (e.g. blood) into lipid environments that are highly fluid, especially when the environment is acidic. In acidic environments PV-10 is protonated, and therefore lipid-soluble; at neutral pH or higher it exists as a salt, and is therefore hydrophilic.

Because cancer cells exhibit significantly higher metabolism than normal cells, they require abnormally high levels of membrane transport activity. To transport nutrients through the cellular membrane, the lipid composition of the membrane must become more fluid, a change that allows PV-10 to transit the cellular membrane of the diseased cells. Once inside the cancer cell, the lysosomal membrane becomes a particularly attractive sink for intracellular PV-10 since the lysosomes’ acidic environment traps PV-10 in its protonated, lipophilic form. Once PV-10 accumulates inside the lysosomes their integrity is disrupted and the acidic hydrolases are released into the cell, as shown by Wachter et al.[v] The cancer cell is quickly destroyed by autophagy.

Through its action on and in lysosomes, PV-10 selectively targets and destroys cancer cells by tapping into natural mechanisms that are radically different from those exploited by typical anti-cancer agents. Chemotherapy destroys cancer cells by poisoning them or attacking the cells’ genetic material (hence the extreme carcinogenicity of most anticancer drugs). PV-10 does not enter the cell nucleus and has the wrong charge for binding to nucleic acids, and therefore is not a carcinogen. Because of the agent’s specificity, systemic side effects are minimal.

PV-10 is the first practical treatment to take advantage of Fossel’s discovery of the Achilles heel of cancer. PV-10 is currently entering Phase 2 clinical trials for melanoma, having achieved outstanding safety and efficacy results in initial Phase 1 studies.

While the death rates for many cancers have been steadily decreasing over the past three decades, the death rate for melanoma increased approximately 25% between 1975 and 2000.  There have been no substantial improvements in drugs licensed for use in melanoma for over 30 years. PV-10 shows great promise to change the paradigm in the treatment of this very deadly cancer. The Achilles heel, as demonstrated by Fossel, may now be exploited using a PV-10, a practical, effective, broad spectrum, and safe anticancer treatment.

[i] Cancer Research 54 (1994) 1240-1248.
[ii] Neoplasia 5 (2003) 533-545.
[iii] Cancer Research 65 (2005) 2993-2995.
[iv] Melanoma Research 16 (2006) S8.
[v] SPIE 4622 (2002) 112–18.

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