Studi relativi al potere antiacido del bicarbonato di sodio nei tumori:
Anne McLean, “Malignant gliomas display altered pH regu1ation byè NHE1 compared with non transformed astrocytes (Am J Physiol Cell Physiol 278: C676-C688, 2000).
Marion Stubbs, “Causes and consequences of tumour acidity and implications for treatment”, Molecular Medicine: Today, January 2000 (vol.6).
Robert J. Gillies, “Causes and consequences of hypoxia and acidity in turners - Novartis Foundatíon symposium”, Molecular Medicine Vol.7 N° 2 February 2001; “Causes and consequences of hypoxia and acìdity in tumour microenvironments”.
J.R. Griffiths, “Causes and consequences of hypoxia and acìdity in tumour microenvironments”, Glia 1994 Nov:12(3):196-210.
Tannock, I.F., “Acid pH in tumors and its potential for therapeutic exploitation”, Cancer Res 1989 Aug 15;49(16):4373-84.
Raghunand, N., “Enhancement of chemotherapy by manipulation of tumour pH”, Br J Cancer 1999 Jun;80(7):1005-11.
Davydova, I.G., “Dynamics of bioelectric activity of the brain and erythrocyte ultrastructure after intravenous infusion of sodium bicarbonate to oncologic patients.” Biull Eksp Biol Med 1992 Apr;113(4):352-5.
Davydova, I.G., “Characteristics of the effects of artificial alkalosis on electrical activity of the brain and ultrastructure of blood cells in oncologic patients”, Vestn Ross Akad Med Nauk 1995;(4):24-5.
Star, R.A., “Regulatory volume decrease in the presence of HCO3- by single osteosarcoma cells UMR-106-01”, J Biol Chem 1992 Sep 5;267(25):17665-9.
LeBoeuf, R.A., “Intracellular acidification is associated with enhanced morphological transformation in Syrian hamster embryo cells”, Cancer Res 1992 Jan 1;52(1):144-8.
Raghunand, N., “Acute metabolic alkalosis enhances response of C3H mouse mammary tumors to the weak base mitoxantrone.” Neoplasia. 2001 May-Jun;3(3):227-35.
Raghunand, N., “pH and chemotherapy pH and chemotherapy” Novartis Found Symp. 200 1;240:199-21 l; discussion 265 -8.
Raghunand, N., “Enhancement of chemotherapy by manipulation of tumour pH.” Br J Cancer. 1999 Jun;80(7):1005-1 I.
Raghunand, N., “Tumor acidity, ion trapping and chemotherapeutics. IL pll-dependent partition coefficients predict importance of ion trapping on pharmaeokinetics of weakly basic chemotherapeutie agents.” Bíochem Pharmacol. 2003 Oct 1;66(7):1219-29.”
Mahoney, B.P., “Tumor acidity, ion trapping and chemotherapeutics. I. Acid plì affects the distribution of ehemotherapeutic agents in vitro.” Biochem Phannacol. 2003 Oct 1;66(7):1207-18.
Schornack, P.A., “Contributions of cell metabolism and H+ diffusion to the acidic pH of tumors.” Neoplasia. 2003 Mar-Apr;5(2):135-45.
Giffles, R.J., “MRI of the tumor microenvironment.” J Magn Reson Imaging 2002 Dec; 16(6):75 l.
Torigoe, T., “Vacuolar H(+)-ATPase: funetional mechanisms and potential as a target for cancer chemotherapy.” Anticancer Drugs. 2002 Mar; 13 (3):23 7-43.
Griffiths, J.R., “Why are cancers acidic? A carrier-mediated diffusion model for H+ transport in the interstitial fluid.” Novartis Found Symp. 200 1;240:46-62; discussion 62-7, 152-3.
Webb, S.D., “Modelling tumour acidity and invasion.” Novartis Found Symp. 2001;240:169-8 l; discussion 181-5.
Gillies, R.J., “The tumour microenvironment: causes and consequences of hypoxia and acidity. Introduction.” Novartis Found Symp. 200 1;240:1-6.
Gillies, R.J., “Causes and consequences of hypoxia and acidity in tumors” Novartis Foundation symposium. Trends Mol Med. 2001 Feb;7(2):47-9.
Griffiths, JR. “Causes and consequences of hypoxia and acidity in tumour microenvironments. Bioessays. 2001 Mar;23(3):295-6.
Gillies, R.J., “Causes and effects of heterogeneous perfusion in tumors.” Neoplasia. 1999 Aug; 1 (3):197-207.
Stubbs, M., “Causes and consequences of tumour acidity and implications for treatment.” Mol Med Today. 2000 Jan;6(1):15-9
Stubbs, M., “Causes and consequences of acidic ph in tumors: a magnetic resonance study.” Adv. Enzyme Regul. 1999;39;13-30.
Webb, S.D., “Mathematical modelling of tumour acidity: regulation of intracellular pH.” J Theor Biol. 1999 Jan 21; 196(2);237-50.
Yamagata, M., “The contribution of lactic acid to acidification of tumours: studies of variant cells lacking lactate dehydrogenase.” Br J Cancer. 1998 Jun;77(11):1726~3 I.
Martin, G.R., “Non invasive measurement of interstitial pH profiles in normal and neoplastie tissue using fluorescence ratio imaging microscopy.” Cancer Res. 1994 Nov 1;54(21):5670-4.
Boyer, M.J., “Regulation of intracellular pH in subpopulations of cefis derived from spheroids and solid tumours.” Br J Cancer. 1993 Nov;68(5):890-7.
Newell, K., “Studies with gIyeolysis-dericient celIs suggest that production of lactic acid is not the only cause of tumor acidity.”
Enhancement of chemotherapy by manipulation of tumour pH.
Raghunand N, He X, van Sluis R, Mahoney B, Baggett B, Taylor CW, Paine-Murrieta G, Roe D, Bhujwalla ZM, Gillies RJ. - Arizona Cancer Center, Tucson 85724-5024, USA.
The extracellular (interstitial) pH (pHe) of solid tumours is significantly more acidic compared to normal tissues. In-vitro, low pH reduces the uptake of weakly basic chemotherapeutic drugs and, hence, reduces their cytotoxicity. This phenomenon has been postulated to contribute to a 'physiological' resistance to weakly basic drugs in vivo. Doxorubicin is a weak base chemotherapeutic agent that is commonly used in combination chemotherapy to clinically treat breast cancers. This report demonstrates that MCF-7 human breast cancer cells in vitro are more susceptible to doxorubicin toxicity at pH 7.4, compared to pH 6.8. Furthermore 31P-magnetic resonance spectroscopy (MRS) has shown that the pHe of MCF-7 human breast cancer xenografts can be effectively and significantly raised with sodium bicarbonate in drinking water. The bicarbonate-induced extracellular alkalinization leads to significant improvements in the therapeutic effectiveness of doxorubicin against MCF-7 xenografts in vivo. Although physiological resistance to weakly basic chemotherapeutics is well-documented in vitro and in theory, these data represent the first in vivo demonstration of this important phenomenon.
Fluorescence ratio imaging of interstitial pH in solid tumours: effect of glucose on spatial and temporal gradients.
Dellian M, Helmlinger G, Yuan F, Jain RK. - Edwin L Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.
Tumour pH plays a significant role in cancer treatment. However, because of the limitations of the current measurement techniques, spatially and temporally resolved pH data, obtained non-invasively in solid tumours, are not available. Fluorescence ratio imaging microscopy (FRIM) has been used previously for noninvasive, dynamic evaluation of pH in neoplastic tissue in vivo (Martin GR, Jain RK 1994, Cancer Res., 54, 5670-5674). However, owing to problems associated with quantitative fluorescence in thick biological tissues, these studies were limited to thin (50 microns) tumours. We, therefore, adapted the FRIM technique for pH determination in thick (approximately 2 mm) solid tumours in vivo using a pinhole illumination-optical sectioning (PIOS) method. Results show that (1) steep interstitial pH gradients (5 microns resolution), with different spatial patterns, exist between tumour blood vessels; (2) pH decreased by an average of 0.10 pH units over a distance of 40 microns away from the blood vessel wall, and by 0.33 pH units over a 70 microns distance; (3) the maximum pH drop, defined as the pH difference between the intervessel midpoint and the vessel wall, was positively correlated with the intervessel distance; (4) 45 min following a systemic glucose injection (6 g kg-1 i.v), interstitial pH gradients were shifted to lower pH values by an average of 0.15 pH units, while the spatial gradient (slope) was maintained, when compared with preglucose values. This pH decrease was not accompanied by significant changes in local blood flow. pH gradients returned to near-baseline values 90 min after glucose injection; (5) interstitial tumour pH before hyperglycaemia and the glucose-induced pH drop strongly depended on the local vessel density; and (6) sodium bicarbonate treatment, either acute (1 M, 0.119 ml h-1 for 3 h i.v.) or chronic (1% in drinking water for 8 days), did not significantly change interstitial tumour pH. Modified FRIM may be combined with other optical methods (e.g. phosphorescence quenching) to evaluate non-invasively the spatial and temporal characteristics of extracellular pH, intracellular pH and pO2 in solid tumours. This will offer unique information about tumour metabolism and its modification by treatment modalities used in different cancer therapies.
J Pain Symptom Manage 1996 Jul;12(1):11-7 Related Articles, Books, LinkOut
Comment in: J Pain Symptom Manage. 1997 Jun;13(6):316-8
Effects of induced metabolic alkalosis on perception of dyspnea during flow-resistive loading.
Taguchi N, Ishikawa T, Sato J, Nishino T. - Department of Anesthesiology, School of Medicine, Chiba University, Japan.
Treatment of dyspnea in patients with advanced cancer is an important issue. The purpose of the present study was to assess the effect of induced-metabolic alkalosis produced by administration of sodium bicarbonate on dyspneic sensation. In seven healthy subjects, dyspnea was induced by having them breathe with a flow-resistive load (24 cm H2O/L/sec) for 6 min before and after administration of sodium bicarbonate (0.5 mmol/kg, per os+2 mmol/kg, IV). The intensity of dyspnea was rated using a visual analogue scale (VAS). The VAS scores and minute ventilation during loaded breathing after administration of sodium bicarbonate were significantly lower than those before administration of sodium bicarbonate. These results indicate that induced metabolic alkalosis may alleviate the intensity of dyspneic sensation by a reduction in ventilatory drive.
Diminuzione del volume in presenza di -HCO3 in cellule di osteosarcoma
Si registra simultaneamente la variazione di voume e di Ph intracellulare, per studiare il ruolo di HCO3- nella diminuzione del volume cellulare.
L’aumento di Ph intracellulare – risulta – coincide con una diminuzione del volume cellulare.
Appare evidente, in questo modo, il coinvolgimento del Na+ (HCO3-) nella regolazione del volume cellulare.
J Biol Chem 1992 Sep 5;267(25):17665-9 Related Articles, Books, LinkOut
Regulatory volume decrease in the presence of HCO3- by single osteosarcoma cells UMR-106-01.
Star RA, Zhang BX, Loessberg PA, Muallem S. - Department of Medicine, University of Texas Southwestern Medical Center, Dallas 75235-9040.
The technique for the simultaneous recording of cell volume changes and pHi in single cells was used to study the role of HCO3- in regulatory volume decrease (RVD) by the osteosarcoma cells UMR-106-01. In the presence of HCO3-, steady state pHi is regulated by Na+/H+ exchange, Na+ (HCO3-)3 cotransport and Na(+)-independent Cl-/HCO3- exchange. Following swelling in hypotonic medium, pHi was reduced from 7.16 +/- 0.02 to 6.48 +/- 0.02 within 3.4 +/- 0.28 min. During this period of time, the cells performed RVD until cell volume was decreased by 31 +/- 5% beyond that of control cells (RVD overshoot). Subsequently, while the cells were still in hypotonic medium, pHi slowly increased from 6.48 +/- 0.02 to 6.75 +/- 0.02. This increase in pHi coincided with an increase in cell volume back to normal (recovery from RVD overshoot or hypotonic regulatory volume increase (RVI)). The same profound changes in cell volume and pHi after cell swelling were observed in the complete absence of Cl- or Na+, providing HCO3- was present. On the other hand, depolarizing the cells by increasing external K+ or by inhibition of K+ channels with quinidine, Ba2+ or tetraethylammonium prevented the changes in pHi and RVD. These findings suggest that in the presence of HCO3-, RVD in UMR-106-01 cells is largely mediated by the conductive efflux of K+ and HCO3-. Removal of external Na+ but not Cl- prevented the hypotonic RVI that occurred after the overshoot in RVD. Amiloride had no effect, whereas pretreatment with 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) strongly inhibited hypotonic RVI. Thus, hypotonic RVI is mediated by a Na+(out)-dependent, Cl(-)-independent and DIDS-inhibitable mechanism, which is indicative of a Na+(HCO3-)3 cotransporter. This is the first evidence for the involvement of this transporter in cell volume regulation. The present results also stress the power of the new technique used in delineating complicated cell volume regulatory mechanisms in attached single cells.
Effetto dell’alcalosi artificiale nell’attività del cervello e nelle cellule del sangue in pazienti oncologici: Vengono studiati 40 pazienti oncologici, di differenti istotipi, sedi e dimensioni.
Il lavoro evidenzia che i pazienti hanno un’acidosi intracellulare generalizzata, che può essere diminuita con l’alcalinizzazione del plasma.
Vestn Ross Akad Med Nauk 1995;(4):24-5 Related Articles, Books, LinkOut
[Characteristics of the effects of artificial alkalosis on electrical activity of the brain and ultrastructure of blood cells in oncologic patients]. [Article in Russian]
Davydova IG, Kassil' VL, Filippova NA, Barinov MV.
The authors examined 40 patients with malignant tumors of various histogenesis, sites and extent, as well as 5 patients with benign tumors and other non-tumorous diseases. They also studied their electroencephalography and peripheral blood lymphocytic and erythrocytic ultrastructure in metabolic alkalosis temporarily induced by intravenous sodium hydrogen carbonate. In cancer patients without late metastases, alkalosis caused a transient normalization of previously altered electroencephalography, erythrocyte disaggregation and substantially reduced the count of killer cells in small and middle lymphocytes. These findings suggest that patients with malignant neoplasms have a generalized intracellular acidosis which can be temporarily abolished by plasma alkalinization.
Cancer Res 1989 Jan 1;49(1):205-11 Related Articles, Books, LinkOut
Requirement of the Na+/H+ exchanger for tumor growth.
Rotin D, Steele-Norwood D, Grinstein S, Tannock I. - Department of Medicine and Medical Biophysics, Ontario Cancer Institute, Toronto, Canada.
The Na+/H+ exchanger is involved in a variety of cellular processes, including regulation of intracellular pH and possibly the control of cell growth and proliferation. To study the role of the Na+/H+ exchanger in tumor growth, human sodium proton exchanger-deficient (HSPD) mutants were derived from the human bladder carcinoma cell line MGH-U1 (EJ) by the proton suicide selection technique (J. Pouyssegur et al., Proc. Natl. Acad. Sci. USA, 81: 4833-4837, 1984). The HSPD cells were approximately 40% larger and contained approximately 70% more DNA than the parental cells. They were unable to grow in vitro in the absence of bicarbonate at pH less than 7.0, whereas the parental cells grew well at pH greater than or equal to 6.6. This difference in acid sensitivity was abolished in the presence of bicarbonate. In contrast to the parental MGH-U1 cells, the Na+/H+-deficient HSPD cells either failed to grow tumors, or showed severely retarded tumor growth when implanted into immune-deprived mice. This difference in tumor growth was not attributed to differences in cell size and DNA content, because Na+/H+ exchange-competent large cells (HLC), derived during the same proton suicide selection process as the HSPD cells, grew tumors at a rate close to that of the parental cells. Cells derived from the few tumors which grew after implantation of HSPD mutant cells were revertants which had regained Na+/H+ activity. HSPD cells also failed to form spheroids in culture, and the only spheroid formed consisted of revertant cells which had regained both Na+/H+ exchange activity and tumorigenic capacity. These results suggest that the Na+/H+ exchanger is important for tumor growth.
Eur J Biochem 1987 Dec 30;170(1-2):43-9 Related Articles, Books
Properties of the Na+-dependent Cl-/HCO3- exchange system in U937 human leukemic cells.
Ladoux A, Krawice I, Cragoe EJ Jr, Abita JP, Frelin C. - Institut National de la Sante et de la Recherche Medicale Unite 204, Hopital Saint-Louis, Paris, France.
U937 cell possess two mechanisms that allow them to recover from an intracellular acidification. The first mechanism is the amiloride-sensitive Na+/H+ exchange system. The second system involves bicarbonate ions. Its properties have been defined from intracellular pH (pHi) recovery experiments, 22Na+ uptake experiments, 36Cl- influx and efflux experiments. Bicarbonate induced pHi recovery of the cells after a cellular acidification to pHi = 6.3 provided that Na+ ions were present in the assay medium. Li+ or K+ could not substitute for Na+. The system seemed to be electroneutral. 22Na+ uptake experiments showed the presence of a bicarbonate-stimulated uptake pathway for Na+ which was inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonate. The bicarbonate-dependent 22Na+ uptake component was reduced by depleting cells of their internal Cl- and increased by removal of external Cl-. 36Cl- efflux experiments showed that the presence of both external Na+ and bicarbonate stimulated the efflux of 36Cl- at a cell pHi of 6.3. Finally a 36Cl- uptake pathway was documented. It was inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonate (K0.5 = 10 microM) and bicarbonate (K0.5 = 2 mM). These results are consistent with the presence in U937 cells of a coupled exchange of Na+ and bicarbonate against chloride. It operates to raise the intracellular pH. Its pHi and external Na+ dependences were defined. No evidence for a Na+-independent Cl-/HCO3- exchange system could be found. The Na+-dependent Cl-/HCO3- exchange system was relatively insensitive to (aryloxy)alkanoic acids which are potent inhibitors of bicarbonate-induced swelling of astroglia and of the Li(Na)CO3-/Cl- exchange system of human erythrocytes. It is concluded that different anionic exchangers exist in different cell types that can be distinguished both by their biochemical properties and by their pharmacological properties.
L’acidificazione intracellulare è associata ad un aumento di trasformazioni morfologiche nelle cellule embrionali di criceto siriano
Lo studio indica che le cellule di criceto possiedono attività regolatorie intracellulari, e che l’acidificazione cellulare gioca un ruolo nell’aumento di frequenza delle trasformazioni osservate nelle cellule coltivate in condizioni di acidità.
Cancer Res 1992 Jan 1;52(1):144-8 Related Articles, Books
Intracellular acidification is associated with enhanced morphological transformation in Syrian hamster embryo cells.
LeBoeuf RA, Lin PY, Kerckaert G, Gruenstein E. - Procter and Gamble Co., Miami Valley Laboratories, Cincinnati, Ohio 45239-8707.
A series of studies has indicated that the frequency of morphological transformation induced by chemical carcinogens in early passage Syrian hamster embryo (SHE) cells is significantly higher when these cells are cultured in medium of reduced bicarbonate concentration and pH (6.70) compared with cells cultured in medium of higher pH. It has also been shown that intercellular gap junctional communication is decreased in these cells when they are cultured at pH 6.70 compared with medium of higher pH. The purpose of the studies reported here was to characterize the effect of changing extracellular pH on intracellular pH in SHE cells. The frequency of morphological transformation induced by benzo(a)pyrene was established at various extracellular pHs and compared with intracellular pH values. Cells cultured in medium of pH ranging from 6.70 to 7.35 were loaded with the pH-sensitive fluorescent dye 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein, and either the steady-state intracellular pH values or the kinetics of change in intracellular pH following refeeding of the cultures with medium of pH ranging from pH 6.70 to pH 7.35 was monitored via image analysis techniques. Results from these studies indicate that, at culture medium pH above 6.95, SHE cells were relatively insensitive to changes in extracellular pH, maintaining an intracellular pH of 7.30 to 7.35 in medium containing 0% serum or pH 7.05 to 7.10 in medium containing 20% fetal bovine serum. At extracellular pHs below 6.95, intracellular pH decreased and, in the presence of serum, equilibrated with extracellular pH. The decrease in intracellular pH was closely associated with an increase in benzo(a)pyrene-induced morphological transformation frequency observed in parallel studies. These results indicate that SHE cells have active intracellular pH regulatory activities and suggest that intracellular acidification plays a role in the increased frequency of transformation observed in SHE cells cultured under acidic conditions.
Dinamiche dell’attività bioelettrica del cervello e dell’ultrastruttura eritrocitaria, dopo infusione di bicarbonato di sodio in pazienti oncologici
Partendo dall’ipotesi di un’acidosi intracellulare generalizzata, 23 paziente affetti da neoplasia in diverse sedi anatomiche e di differenti tipi istologici, sono stati trattati con NaHCO3.
L’alcalosi metabolica ha indotto miglioramento nellEEG e nelle alterazioni di aggregazione eritrocitaria.
Il risultato conferma l’ipotesi di partenza.
Biull Eksp Biol Med 1992 Apr;113(4):352-5
[Dynamics of bioelectric activity of the brain and erythrocyte ultrastructure after intravenous infusion of sodium bicarbonate to oncologic patients]. - [Article in Russian]
Davydova IG, Kassil' VL, Raikhlin NT, Filippova NA.
23 patients with malignant tumors of different location and histogenesis were investigated. There were no metastases in 9 cases. 10 patients had metastases in regional areas and 4--distant. The results were compared with those obtained in 4 patients with nonmalignant diseases. EEG, blood gases, plasma acid--base balance and ultrastructure of erythrocytes were explored before and after intravenous infusion of 4.2% sodium bicarbonate solution. The metabolic alkalosis induced amelioration of EEG, which was changed basically, the condense of pre-membrane layer disappeared or decreased in erythrocytes, and disaggregation of erythrocytes took place in cancer patients vs those with nonmalignant tumors. The results confirm the suggestion of generalized intracellular acidosis in malignant tumor patients. This acidosis can be temporarily avoided or diminished artificially by blood alkalosis.
Liver Transpl Surg 1999 Mar;5(2):151-2 Related Articles, Books
Prolonged lactic acidosis after extended hepatectomy under in situ hypothermic perfusion.
Davidson BR, Rai R. - Department of Surgery, The Royal Free Hospital, London, England.
46-year-old woman underwent right extended hepatectomy under total vascular occlusion with in situ hypothermic perfusion for colorectal metastasis. Immediately after surgery, she developed severe lactic acidosis, which required correction with sodium bicarbonate solution and ventilatory support for 36 hours. After 2 days, her lactate normalized, and the acidosis was corrected. She made an uneventful recovery. Persistent lactic acidosis after major hepatic resection under in situ hypothermic perfusion is a rare but reversible problem.
Cancer Res 1998 May 1;58(9):1901-8 Related Articles, Books, LinkOut
Heterogeneity of intracellular pH and of mechanisms that regulate intracellular pH in populations of cultured cells.
Lee AH, Tannock IF. - Department of Medical Biophysics, Ontario Cancer Institute, Toronto, Canada.
solid tumors are known to exist in a microenvironment that may be acidic and
depend on membrane-based mechanisms (Na+/H+ antiport and Na+-dependent Cl-/HCO3-
exchanger) that regulate intracellular pH (pHi). We have used the fluorescent pH
indicator 2',7'-bis-(2-carboxyethyl) 5 (and 6)-carboxyfluorescein and flow
cytometry to study the distribution of pHi and the activity of these pHi-regulating
mechanisms among populations of murine mammary sarcoma (EMT6), human breast
cancer (MCF-7), and Chinese hamster ovary cells exposed to different levels of
extracellular pH (pHe). Cells were exposed to Na+ buffer in the presence or
absence of HCO3- and of 5-(N-ethyl-N-isopropyl)-amiloride (a potent inhibitor of
the Na+/H+ antiport) to determine the relative importance of each exchanger in
the regulation of pHi. Our results indicate that: (a) the distribution of pHi at
any value of pHe is broader than can be accounted for by machine noise; (b)
cells maintain levels of pHi that are higher than pHe under acidic conditions;
(c) the distribution of pHi is narrower when the Na+-dependent Cl-/HCO3-
exchanger is active; and (d) populations that are derived from selected cells
with values of pHi at lower and higher ends of the pHi distribution generate pHi
distributions that are similar to those of controls, suggesting a stochastic
variation in the activity of membrane-based mechanisms that regulate pHi.
Our data suggest that the Na+-dependent Cl-/HCO3- exchanger is the dominant mechanism for regulation of pHi under moderately acidic conditions such as may occur in the microenvironment of solid tumors
October 8, 2007
How A Benign Fungus Can Become Life-Threatening
Researchers at the Agency for Science, Technology and Research’s Institute
of Molecular and Cell Biology have discovered new molecular mechanisms that
provide a more detailed understanding of how the normally benign Dr.
Jekyll-like fungus known as Candida albicans transforms into a serious and
often life-threatening Mr. Hyde-like form.
C. albicans can cause serious and potentially life-threatening infections in
the mouth, blood and other tissues of people who are undergoing cancer
chemotherapy or radiation treatments, or who have developed AIDS or other
diseases that damage the immunity of the individual.
In two separate papers recently published in Developmental Cell and the EMBO
journal, the team of scientists led by Wang Yue, principal investigator at
IMCB, have managed to reveal previously unknown mechanisms which are
responsible for causing the infectious phase of C. albicans.
The fungus starts its ‘attack’ on a patient by changing its oval shape into
a filamentous form, which has thin, threadlike appendages emerging from the
cell body. Wang’s team, who has been studying C. albicans for more than
seven years, was responsible for identifying the master “controller” protein
called Hgc1 in 2004.
This “controller” functions like a regulator and tells the fungus when to
start the transformation from the harmless oval shape to the infectious
“One question remained, however - how does it activate the cellular
machineries that determine the fungal cell shape?” said Wang.
Wang’s team found the answer to this question in two proteins called Rga2
and Cdc11. They discovered that they each function like a switch on two
different cellular machineries that normally determines cell shape. “The
master regulator Hgc1 acts like the ‘finger’ that flips the switches to
start the infection process,” said Wang.
“Our findings have uncovered detailed molecular mechanisms which define how
these two proteins interact with the master ‘controller’ to cause
infections. This has opened new opportunities for us to investigate further
into a new range of therapeutic targets for fungal infections,” explained
In the same issue of Developmental Cell, the team’s work was given an expert
mention by a leading C. albicans researcher, Dr. Peter Sudbery, stating its
importance in bringing awareness of the cellular processes that is necessary
for C. albicans to transform to its infectious state.
In addition, the new knowledge of the detailed interaction of these proteins
with other cellular machineries has also revealed critical information on
how cells in general determine their shape, a fundamental question in
biology as Rga2 and Cdc11 are also found in nearly all eukaryotic organisms.
Largely due to the AIDS pandemic in the last 25 years, the once nearly
harmless and commensal fungus Candida albicans has become one of the most
prevalent microbial pathogens in AIDS patients, causing life-threatening
infections with high death rate, especially in infected children.
References: XD Zheng, RTH Lee, YM Wang, QS Lin, and Y Wang. Phosphorylation
of Rga2, a Cdc42 GAP, by CDK/Hgc1 is crucial for Candida albicans hyphal
growth. The EMBO Journal 26, 3760-3769 (2007).
I Sinha, YM Wang, R Philp, CR Li, WH Yap, and Y Wang Cyclin-Dependent
Kinases Control Septin Phosphorylation in Candida albicans Hyphal
Development. Developmental Cell 13: 421-432 (2007).
1: Cancer Res. 2009 Mar 15;69(6):2260-8. Epub 2009 Mar 10.
Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA.
The external pH of solid tumors is acidic as a consequence of increased metabolism of glucose and poor perfusion. Acid pH has been shown to stimulate tumor cell invasion and metastasis in vitro and in cells before tail vein injection in vivo. The present study investigates whether inhibition of this tumor acidity will reduce the incidence of in vivo metastases. Here, we show that oral NaHCO(3) selectively increased the pH of tumors and reduced the formation of spontaneous metastases in mouse models of metastatic breast cancer. This treatment regimen was shown to significantly increase the extracellular pH, but not the intracellular pH, of tumors by (31)P magnetic resonance spectroscopy and the export of acid from growing tumors by fluorescence microscopy of tumors grown in window chambers. NaHCO(3) therapy also reduced the rate of lymph node involvement, yet did not affect the levels of circulating tumor cells, suggesting that reduced organ metastases were not due to increased intravasation. In contrast, NaHCO(3) therapy significantly reduced the formation of hepatic metastases following intrasplenic injection, suggesting that it did inhibit extravasation and colonization. In tail vein injections of alternative cancer models, bicarbonate had mixed results, inhibiting the formation of metastases from PC3M prostate cancer cells, but not those of B16 melanoma. Although the mechanism of this therapy is not known with certainty, low pH was shown to increase the release of active cathepsin B, an important matrix remodeling protease.
PMID: 19276390 [PubMed - in process]