Molecular Refrigerators: a New Approach in Anti-Cancer Therapy

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Hypothesis

Molecular refrigerators: a new approach in anti-cancer therapy

Biomedical Sciences U Lucia*

Abstract This thermalisation is suggested These genes are also expressed in Introduction as anti-cancer therapy. The tempera- pre-neoplastic states. The temperature difference be- ture variation is evaluated by using • There exist genes related to the tween normal and cancer cells was the entropy generation approach. growing ability of the cancer at its proven to be one of the fundamen- Conclusion • place along with their invasive be- tal quantities in the cancer growth. The results obtained represent a new haviour with high density. The allosteric transition is a confor- approach to the study of the cancer The cancer has high mitosis on ap- mational change of a protein condi- and for the development of new anti- optosis ratio. cancer therapy based on molecular • A fundamental role of the interac- an enzyme, two different parts can refrigeration. tion between the cancer and its oscillatetioned to around bind at their a specific equilibrium site; in • environment has experimentally Introduction been pointed out7. these parts increase their oscillating Cells interact with their environment As a consequence of these results, amplitudes,state; if the decreasing temperature in their increases, func- using powerful biochemical process- cancer can be described as a non- tionality. This paper discusses a new ing systems. Understanding how linear dynamic system in non-equi- method for anti-cancer therapy. cells interact with and respond to the librium thermodynamic states, with changes in their environment is es- Hypothesis following characteristics: complex- The entropy generation approach sential to develop new approaches ity8, robustness9, adaptability10,11 and has been used in order to evaluate in biotechnology and medicine1,2. self-organisation5. Consequently, the the stationary conditions of tumour- Consequently, there exists a con- study of its stationary states results al cells in relation to the transport tinuous growing interest in applica- fundamental step in order to control processes. The tumoural systems can tions of process system engineering the cancer behaviour. So, the entropy assume all the values of volume, tem- techniques to biomedical problems3. generation approach12 can be used in perature, chemical reaction rate and In particular, there is a great inter- order to introduce a non-equilibrium the time of chemical reaction inside est in the analysis of the protein in thermodynamic approach to the can- - relation to biological events, such as cer analysis. side of this range, the cancer cannot - The cells reach their optimality by developits stationary and cell range dies. of variation; out tion and protease cleavage4. ligandThe binding,carcinogenesis enzymatic has modifica always Evaluation of Hypothesis pattern through the metabolic net- The control over these physical– been considered as the result of the workmeans by of using a redistribution the pattern of catalyticthe flow chemical processes can be obtained development of abnormal cell mor- - by using molecular refrigerators, phology towards metastatic invasive tations and genetic rearrangements which help control the temperature phenotype by means of increase in areand fundamentalregulatory proteins; for an organismindeed, mu to of the cells. The aim is to maintain the their number and density. In the last adapt to environmental conditions. temperature of a normal cell and not decades, many other characteristics This paper discusses molecular re- to allow the cell to increase its tem- were discovered related to cancer or frigerators as a new approach in anti- perature up to the cancer state. This genes behaviour5,6: cancer therapy. brings about conformation changes There are precursors, often pre- in a protein by supplying free energy sent in cancers, which allow us to Hypothesis on one site of the molecule, required • point out the relationship between In this paper, we suggest a molecular for driving the cooling process. cancer cells and their stroma. cooling approach to cancer therapy. There will be blood vessel forma- The recently obtained thermody- * Corresponding author Email: [email protected] tion, even if avascular tumour namic results and molecular cooling • growth conditions still exist. will be summarized and suggested DipartimentoEnergia, Politecnico di Torino, CorsoDucadegli Abruzzi 24, 10129 Torino, There are cancer genes, which reg- in relation to a possible new anti- Italy ulate mitosis and apoptosis. cancer therapy, • Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

Lucia U. Competing interests: none declared. Conflict of interests: none declared. interests: none declared. Conflict of interests: Competing the final manuscript. preparation, read and approved and design, manuscript conception to All authors contributed rules of disclosure. ethical Ethics (AME) for Medical the Association All authors abide by For citation purposes: Molecular refrigerators: a new approach in anti-cancer therapy. OA Medical Hypothesis 2013 Jun 01;1(1):9. Page 2 of 4

Hypothesis

Evaluation of Hypothesis is on autopoietic pathways, be- velocity, ρi is the concentration of the The author has referenced some of his cause there exist continuous cycles i-th species and os and is means out- own studies in this hypothesis. These • for generation and autocatalytic side and inside the cell, respectively, referenced studies have been conduct- τ3 is the lifetime of this process, η is ed in accordance with the Declaration has exergy enhancement or main- ẋB of Helsinki (1964) and the protocols tenance,feedbacks; because it exports entro- denotes the centre of mass velocity • the average viscosity coefficient, of these studies have been approved by py products which exceed or equal of all components in the cell, de cy- the relevant ethics committees related the entropy production of the in- toplasm layer and r the mean cell ra- to the institution in which they were gested free energy source and de- dius, τ4 is the lifetime of this process, performed. All human subjects, in these Ni is the number per unit time and referenced studies, gave informed con- presents material conservation volume of the i-th chemical reaction sent to participate in these studies. andcreases maintains its internal its entropy;physical andcom- and A The recently obtained results in the • ponents, because it maintains its variation of the standard Gibbs free thermodynamic approach to cancer structural basis for storing the ac- energy. is the affinity, evaluated as the can be summarized as follows13–17: quired organisational exergy. From this result it follows that if we can decrease the value of the temper- There is a possibility to convert an Cells are chemical engines in which ature difference between the normal exergy source to entropy, where and the cancer cells, mathematically • exergy is the energy that the sys- occur. By using the entropy genera- represented by the term DT, we can tem can really use18. tionspecific extrema ordered theorem chemical8, the reactions maxi- control the cancer growth. Of course, The biochemical reactions produce mum volume reached by the cancer this approach can be improved, but or consume external metabolites, systems is obtained as16,17: • accumulated inside the system, and αγ()1+−T  ∆T the cooling approach by molecular they connect internal metabolites VV≤+ i +V (1) ci βε+ i  motors.it can be considered as a first step in in constant concentrations in the   Ti cells at their steady states. So, liv- Where Vc is the maximum volume Consequences of Hypothesis ing systems must exchange exergy Many chemical processes in cells of the cancer and Vi is the initial vol- and matter through their boundary. use large molecules23 (proteins, en- ume, Ti the initial temperature and Consequently, cancer is also an open DT the temperature difference be- zymes, etc.). A chemical or physical system which is in a state far from tween a normal and a cancer cell20–22 process which occurs at one border thermodynamic equilibrium14–17. and of a protein can lead to a change in The cancer is a system which can be analysed by using a set of uL2 x ατ= th the same protein, with a consequent • subsystems17. 6 1 interactionthe configuration among atatoms another in the site mol of- The life of such systems is an organ- ρµ()− µ ecule23. This effect is the well-known isational process, result of system ∑ ii,,os iis β = i τ x allosteric transition, a conformation- • cooperation between components, 2 th dm al change of a protein conditioned to with an interconnection between 2 x B sub-systems and system, such that γπ= 4 ητ3 interesting in the regulation of en- for survival the system must ex- rde zymebind at activity, a specific in motorsite, and proteins, it is very in port equal or more entropy prod- ετ= 4 ∑NiiiA (2) ion transport through membranes, ucts than its sub-system produces, i etc.11. As a consequence of the inter- towards maximum conversion of where τ1 is the lifetime of this action, the atoms have a transition available energy (called exergy) process, ẋth is the molecular thermal between two thermodynamic sta- sources to entropy products. velocity and u the cell volumetric tionary states and the protein reverts internal energy, L typical length of to the rest conformation, while the Consequently, from a thermody- a cell, which can be evaluated as its atoms revert to the rest model and namic point of view, a cell system13–17: mean equivalent diameter, τ2 is the the protein starts again, the protein

is open, because it exchanges en- lifetime of this process, μi chemical needs to be supplied with free ener- 11 potential of the i-th species, dm is gy to complete the cycle. • the volume and depth of the mem- The control of these physical– isergy far andfrom mass equilibrium, flows through because its it brane, where the chemical potential chemical processes allows us to use boundaries; is a source of high exergy values iρi(μi,os-μi,is)/dm, especially molecules as molecular refrigerators • occurs in cytoplasm, ẋth is the thermal in order to control the temperature gradient, ∑ and basic materials; Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

Hypothesis of the cells. It must be underlined Discussion in accordance with the data used that this temperature is the differ- The entropy generation approach in reference 29. Now, considering that ence between the temperature of a has been used in order to evaluate DT is the temperature difference be- cancer and normal cell. The aim is to the stationary states for the cancer tween a normal and a cancer cell, for maintain the temperature of a nor- system in relation to its volume and example DT ~ 0.15 ÷ 0.40°C, it follows mal cell and not to allow the cell to temperature. Following the entropy increase its temperature up to the generation extrema theorem19, the temperature30: cancer state. Indeed, the interaction cancer can assume all the values that the cancer cell will reach its final T ~ 310.25 ÷ 310.55 K =37.10 ÷ between two open systems can re- inside a range which represents its 2 sult time-dependent and external- conditions of stability. Outside of 37.40°C for glucose reaction (5) 24,25 1. T ~ 310.24 ÷ 310.49 K = 37.09 ÷ driven . The useful effect results this range, the cancer cannot de- 2 in conformational changes in a pro- velop and the cell dies. This analysis 37.39°C for the palmitic acid reac- 2. tein25,26 by supplying free energy on points out that the geometrical char- tion (6) one site of the molecule required for acteristics (chemical reaction rate So, the frequency ratio useful to 26 driving the cooling process . The and the time of chemical reaction) cool the cancer cell results as ν / chemical reaction in one site of the are fundamental in the growth of 0 ν1 ~ 0.99872 ÷ 0.99952 for both the protein drives the cooling effect to cancer. So, there exists a maximum reactions. another site of the protein. value of volumetric growing after Consequently, the inside tempera- In an enzyme, two different parts which the tumour invades other ture control could represent a new can oscillate around their equilib- parts of the body. approach to anti-cancer therapy. rium state. If the temperature in- Cancer temperature results from In particular, molecular refrigera- creases, these parts increase their the fundamental quantity in the anal- tors could be useful anti-cancer de- oscillating amplitudes, with many ysis of the cancer growth related to vices. Molecular refrigerators can possible vibration modes with a con- be obtained by using many different sequent decrease in the functionality metabolism can be studied by the techniques: of the enzyme. The thermalisation analysisthe exergy of flows.the reactions Indeed, of the oxidation cellular of the oscillator is a process which of the energy substrates28 consider- Catalysis as proposed by Briegel has a characteristic time-dependent ing the oxidation of carbohydrates, li- and Popescu26,27 on the interaction strength between pids and protein, represented by the • - the system and the environment27 reactions of oxidation28,29: posed by Liu and Chen31 and the cooling can occur only if the • ElectromagneticElectric field interaction or ultrasound as pro 20–22 thermalisation time τtherm is less than waves as proposed by Luo C6H12O6 + 6O2 + 2 + • 32 the oscillation time τosc: τtherm << τosc. Molecular machines which be- 27 1. Glucose6H O + 30 P (5) It has been evaluated that after a 2 ATP have as molecular refrigerators to with P the phosphate 30 P →group 6CO of cooling cycle, the temperature of the ATP • be designed interaction site of the enzyme can be ATP reduced up to: C16H32O2 + 23O2 + 2 + • Local inflow of nanoparticles of ∆T v0 2. Palmitic acid ==1 − (3) 16H2O + 106PATP (6) toferrofluids be developed in interaction with T v 106 P → 16CO i 1 Now, considering a normal cell and magnetic field as a new approach with ν0 the oscillation frequency of for example, the cell environmental Conclusion - The results obtained represent a new temperature, T0 = 309.60 K = 36.45°C ing) and ν1 the oscillation frequency of (mean temperature inside the body as approach to the study of the cancer the initial configuration (before cool environmental temperature) and the and to the development of new anti- In order to use this approach as cancer therapy based on molecular cell mean temperature T1 = 309.95 anthe anti-cancer final configuration therapy, (after it is cooling).required K = 36.8°C (mean temperature of a refrigeration. that this temperature variation is the cell inside the human body), have same as in the relation (1), so the fre- been evaluated30,31 - References quency ratio between the initial and perature inside the cell: 1. Wayman JA, Varner JD. Biological sys- with a final tem tems modeling of metabolic and signal- = = follow this theoretical relation: T2 310.10 K 36.95°C for glu- ing networks. Curr Opin Chem Eng. 2013 final configuration is suggested to cose reaction (5) v0 VVci− 1. ≤−1 (4) T2 = 310.09 K = 36.94°C for the 2. Kawahara M, Nagamune T. Engineering v αγ()1+−T Nov;2(4):365–72. 1 i +V palmitic acid reaction (6) of mammalian cell membrane proteins. βε+ i 2. Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)

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