Biography

I completed my doctoral program at the University of Tokyo in 1974 and received PhD in 1974 in Biochemistry from the University of Tokyo. After postdoctoral training at Colorado University Medical Center, I started studies on adaptation strategies of microorganisms to acidic environments at Chiba University as an associate professor in 1978. I studied genetics at the University of Michigan School of Dentistry as a Visiting Researcher in 1985-1986. After professor position was appointed in 1996 at Faculty of Pharmaceutical Sciences, Chiba University, my research has focused on mammalian cell functions under acidic conditions and anti-cancer chemotherapy in acidified nests. I retired from Chiba University in 2012 at the age of 65 due to university regulations and am now a professor emeritus at Chiba University. I worked as an associate editor of International Immunopharmacology published by Elsevier from 2014 to 2024. 
My research is summarized in the book: Hiroshi Kobayashi. 2021. “Molecular Strategies of Creatures to Survive in Acidic Environments: Invitation to the Acidic World”. Cambridge Scholars Publishing. Newcastle upon Tyne. UK. 

Abstract

Many trials to measure the pH of tumor tissues over the past 80 years have shown that solid cancer nests are generally acidified. However, until recently, few trials have been conducted to measure the efficacy of ani-cancer drugs under acidic conditions. It is erroneously accepted that the pH of cytosolic spaces is kept at pH around 7.4 even if the external space is acidified. This is one of reasons why anti-cancer drugs specific to acidified cancer nests have not been focused. We first measured the cytosolic pH of cancer cells growing in acidic medium and found that the cytosolic pH decreases as the acidification of the growth medium. This suggests that some enzymes are working preferentially at internal acidic pH.

Using DNA array techniques, we found that approximately 700 genes among 24,000 genes tested are expressed at a higher level in mesothelioma cells growing in acidic medium. Anti-cancer drugs targeting the enzymes whose expression increases in acidic cancer nests would be effective in cancer treatment with fewer adverse effects on normal cells in the normal tissues whose pH is slightly alkaline around 7.4. 

To confirm this idea, we established the in vitro assay system for screening anti-cancer drugs working in acidic nests, and approximately 300 compounds were examined using various cancer cell lines. Among them, four compounds, lovastatin, cantharidin, manumycin A, and ionomycin, were found to have higher anti-cancer activity at acidic pH compared with pH 7.4. Interestingly, many anti-cancer drugs we are now using showed less efficacy at acidic pH. 
Among the four compounds, we have focused on statins, and found that statins inhibit cancer cell proliferation through the suppression of the RAP1 prenylation but not the inhibition of cholesterol synthesis at acidic pH. 

There are still debates whether statins have anti-cancer activity or not. We found that the effect of statins is conditional, they are effective at acidic conditions but not at pH around 7.4. Therefore, acidity of cancer nests should be always considered when we discuss the efficacy of statins on cancer treatment, especially in a mouse model. 
In addition to the above drugs, we found many drugs whose efficacy is shown to elevate at acidic pH.

We also found that the TCR signaling is affected by external acidity, and acidification of cancer nests should be kept in mind for development of anti-cancer immunotherapy as well.