A nonmainstream approach against cancer

Abstract

The discovery of antibiotics as specific and effective drugs against infectious agents has generated the belief that the famous Paul Erlich theory on magic bullet should be applied to cancer as well. However, after around 60 years of failures in finding a magic bullet against cancer, a question appears mandatory: does the magic bullet against cancer really exist? In trying to understand more on the issue, we propose three discoveries are coming from a nonmainstream approach against cancer. Tumor is acidic, and tumor acidity impairs drugs entering within tumor cells and isolates tumors from the rest of the body. Proton pumps are key in allowing tumor cells to live in the acidic microenvironment. A class of antiacidic drugs, proton pump inhibitors (PPIs), were shown to have a potent anti-tumor effect, through inhibition of proton pumps in tumor cells. PPIs are indeed prodrugs needing acidity to be activated into the active molecule. So they use protonation by H+ as an activating mechanism, while the vast majority of drugs are totally neutralized by protonation. An anti-tumor therapy based on PPI showed to be effective both in vitro and in vivo. Differently from normal cells, cancer cells meet their energy needs in great part by fermentation, and it appears conceivable that hypoxia and low nutrient transform tumor cells into fermenting anaerobes. This suggests that cancer cells are more similar to unicellular organisms, aimed at surviving in a continuous fighting, rather than cooperating, with other cells, as it occurs in the normal homeostasis of our body. We have shown that cancer cells take their fuel by ''cannibalizing'' other cells, either dead or alive, especially when starved and in acidic condition. This finding led to the discovery of a new oncogene TM9SF4 that human malignant cell shares with amoebas. The evidence is accumulating that almost all the cells release extracellular vehicles (EVs), from micro-to nanosize, which shuttle a variety of molecules. Tumor cells, particularly when stressed in their hostile microenvironment, release high levels of EVs, able to interact with target cells in various ways, within an organ or at a distance. They may represent both valuable tumor biomarker and shuttles for drugs with anti-tumor properties. This article wants to burst a real change in future anti-cancer strategies, based on the idea that tumors are much more common features than specific molecular targets.

Effect of Modified Alkaline Supplementation on Syngenic Melanoma Growth in CB57/BL Mice

“…We want to conclude with an emphasis to the fact that the achievement of these results, with a high potential to be translated to the clinical use, was obtained thanks to the nonmainstream approach against cancer, representing a key paradigm of our research group [ 43 ].…”

Microenvironmental pH and Exosome Levels Interplay in Human Cancer Cell Lines of Different Histotypes

“…Together with modulating a range of normal functions, exosomes may be considered as a way our body exploits to interconnect organs and compartments [ 4 ]. However, these natural nanovesicles are actively involved in tumor progression, and inhibition of tumor exosome release may represent an antitumor strategy [ 1 , 12 , 13 ]. The tumor microenvironment is typically acidic, and extracellular acidity is a common phenotype of almost all tumors [ 14 ].…”

Plasmatic exosomes from prostate cancer patients show increased carbonic anhydrase IX expression and activity and low pH

“…Between these adaptive advantages, cancer cells implement a series of strategies, making them very similar to unicellular organisms 8,10 . However, to prevent intracellular H þ accumulation cancer cells upregulates proton exchangers that extrude protons in excess contributing to acidify extracellular tumour microenvironment 9,11,12 . Among these proton exchangers, a primary role is played by CA IX, an enzyme overexpressed in many types of cancers, including prostate cancer, with the potential to represent both a promising tumour biomarker and a specific target for future cancer therapies 13,[30][31][32][33][37][38][39][40][41]44 .…”

“…Moreover, the extracellular acidity induces a selective pressure leading to the clonal selection of cancer cells that can survive in such a hostile condition 7 . Cancer cells survive and proliferate thanks to a series of innate mechanism conceivably common to all malignant tumours [8][9][10] . Among these, the proton pumps play a crucial role, reducing intracellular pH and acidifying the extracellular environment 9,11,12 .…”

“…Cancer cells survive and proliferate thanks to a series of innate mechanism conceivably common to all malignant tumours [8][9][10] . Among these, the proton pumps play a crucial role, reducing intracellular pH and acidifying the extracellular environment 9,11,12 . Therefore, tumour cells up-regulate proton exchangers and transporters throwing out excess protons through Vacuolar ATPase (V-ATPase), Naþ/H þ exchanger (NHE), monocarboxylate transporters (MCTs), cotransporter sodium bicarbonate (NBC), and carbonic anhydrase 9 (CA IX) 2,[11][12][13] .…”