Use of moxifloxacin as a senomorphic drug

Abstract

In vitro experimental studies have shown that moxifloxacin suppresses SASP induced by doxorubicin, a chemotherapeutic agent. Therefore, moxifloxacin may be used as a senomorphic drug. Thus, a drug containing moxifloxacin may be used to inhibit the secretory activity of senescent cells (a senomorphic effect) by suppressing SASP, and it will be possible to use it practically to reduce or eliminate the side effects of chemotherapy and / or radiotherapy in a patient receiving chemotherapy and / or radiotherapy. On the other hand, a drug containing moxifloxacin may be used to reduce the undesirable effects of senescent cells observed in old age.

Description

[0001] USE OF MOXIFLOXACIN AS A SENOMORPHIC DRUG

[0002] Technical Field

[0003] The invention relates to a senomorphic effect of moxifloxacin, which inhibits the secretory activity of the senescent cell by suppressing SASP as a new effect thereof.

[0004] State of the Art

[0005] Cellular senescence is a phenomenon characterized by the loss of cells’ capability of proliferation by exiting from the cell cycle permanently, although they are metabolically and transcriptionally active. This phenomenon is called senescence, and cells that transform into this form are called senescent cells. Senescence is divided into two categories according to the reason of their occurence. The first one is ‘replicative senescence’ (senescence observed in old age) is a type of senescence that occurs after a prolonged proliferation triggered by the intrinsic mechanisms (telomere erosion due to the telomere shortening, deterioration of telomere structure and decreased telomerase expression) in the cell. The second one is ‘stress-induced premature senescence’ , which is a relatively fast-forming senescence type (lasting for a few days) triggered by extrinsic stresses (oncogene activation, oxidative stress, DNA damage, drug therapy) without telomere damage. Characteristic changes are observed in the senescent cells, such as enlarged and flattened multinucleated cell morphology. Another important characteristic feature of senescent cells is that they secrete various substances with strong paracrine effects into the extracellular fluid, such as cytokines, growth factors and matrix metalloproteinases (SASP). The senescent cells have been observed to have proliferative / antiproliferative / migratory effects on the other cells in their microenvironment by secretome secreted by them.

[0006] Studies have shown that different chemotherapeutic agents used in the clinic induce the formation of senescence and cause the development of senescence secretome. There are studies showing that the senescent cell secretome formed by chemotherapeutic drugs induce tumor development on the surrounding cells and / or cause resistance to the chemotherapeutic drugs. On the other hand, senescent cells accumulating in various tissues with aging and the factors secreted from these cells have also been associated with the pathogenesis of many diseases such as type 2 diabetes, cataract, and pulmonary fibrosis. Therefore, the use of so-called senomorphic agents which inhibit the secretory activity of senescent cells is considered as a new therapeutic strategy in the treatment of pathological conditions related to both cancer and aging. Various drugs (metformin, lovastatin, glucocorticoids, etc.) and the potential of drug candidate molecules to become senomorphic drugs have been evaluated in very recent studies conducted for this purpose.

[0007] It has been shown in the literature that there are senomorphic drugs with different mechanisms of action (metformin, simvastatin, glucocorticoids, rapamycin, ruxolitinib, celecoxib). References containing these senomorphic drug reviews are listed below.

[0008] References

[0009] 1 . Laberge, R. M., Zhou, L., Sarantos, M. R., Rodier, F., Freund, A., de Keizer, P. L., Liu,

[0010] S., Demaria, M., Cong, Y. S., Kapahi, P., Desprez, P. Y., Hughes, R. E., Campisi, J. 2012.

[0011] “Glucocorticoids suppress selected components of the senescence-associated secretory phenotype”, Aging cell, 11 (4), 569-78.

[0012] 2. Moiseeva, O., Deschenes-Simard, X., St-Germain, E., Igelmann, S., Huot, G., Cadar,

[0013] A. E., Bourdeau, V., Pollak, M. N., Ferbeyre, G. 2013. “Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK / NF-KB activation”, Aging cell, 12(3), 489-98.

[0014] 3. Liu, S., Uppal, H., Demaria, M., Desprez, P. Y., Campisi, J., Kapahi, P. 2015. “Simvastatin suppresses breast cancer cell proliferation induced by senescent cells”, Scientific reports, 5, 17895.

[0015] 4. Laberge, R. M., Sun, Y., Orjalo, A. V., Patil, C. K., Freund, A., Zhou, L., Curran, S. C., Davalos, A. R., Wilson-Edell, K. A., Liu, S., Limbad, C., Demaria, M., Li, P., Hubbard, G.

[0016] B., Ikeno, Y., Javors, M., Desprez, P. Y., Benz, C. C., Kapahi, P., Nelson, P. S., Campisi, J. 2015. “MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting I L1 A translation”, Nature cell biology, 17(8), 1049-61 .

[0017] 5. Xu, M., Tchkonia, T., Ding, H., Ogrodnik, M., Lubbers, E. R., Pirtskhalava, T., White,

[0018] T. A., Johnson, K. O., Stout, M. B., Mezera, V., Giorgadze, N., Jensen, M. D., LeBrasseur, N. K., Kirkland, J. L. 2015. “JAK inhibition alleviates the cellular senescence- associated secretory phenotype and frailty in old age”, Proceedings of the National Academy of Sciences of the United States of America, 112(46), E6301-E6310.

[0019] 6. Gongalves, S., Yin, K., Ito, Y., Chan, A., Olan, I., Gough, S., Cassidy, L., Serrao, E., Smith, S., Young, A., Narita, M., & Hoare, M. 2021. “COX2 regulates senescence secretome composition and senescence surveillance through PGE2.” Cell reports, 34(11 ), 108860.

[0020] Moxifloxacin (Formula I), which is the subject of the patent application and has been considered as a new senomorphic drug, is currently used in the treatment of infectious diseases due to its antimicrobial activity. Its oral, injection and eve drop forms are available. For moxifloxacin, which is a licensed medicine, no document has been found on the senomorphic activity of moxifloxacin.

[0021] Detailed Description of the Invention

[0022] As a result of the studies carried out by the inventors, it has been found that Moxifloxacin or its pharmaceutically acceptable salt or hydrate has a suppressive effect on the secretory activity of senescent cells, apart from its antimicrobial effect, in other words, it has a senomorphic effect. As a result of in vitro studies, moxifloxacin has been determined to suppress SASP (senescence-associated secretory phenotype of the senescent cells) induced by doxorubicin, a chemotherapeutic agent.

[0023] Therefore, moxifloxacin may be beneficial in cases where adverse effects of SASP developed due to aging and cancer chemotherapy are observed. Moreover, in studies evaluating the activity of SASP, moxifloxacin may be used as an experimental tool to suppress SASP. There are various drugs in the literature that suppress SASP secreted from senescent cells. These are compounds with different mechanisms of action and different chemical structures from each other. Moxifloxacin, which has inhibitory activity on the secretory activity of the senescent cell, is another compound with a completely different structure from these compounds. Considering the clinical use, each drug group may not be used in every patient due to some undesirable effects. To this end, different molecules with similar effects are preferred in the treatment. Moxifloxacin may also be preferred in order to suppress SASP either as a first choice or in cases where other drugs cannot be used. A similar situation exists for the experimental use of compounds that suppress SASP experimentally.

[0024] The combined use of moxifloxacin with chemotherapeutic agents may reduce the side effects of chemotherapeutics and cancer development in cancer patients and increase the survival of patients. In addition, this will facilitate the adherence of cancer patients to treatment. On the other hand, moxifloxacin will also be effective in preventing various pathological conditions caused by senescent cells that occur with aging.

[0025] Moreover, the use of moxifloxacin in the treatment of cancer- and aging-related pathologies in the clinic will contribute to the partial reduction of health expenses related to these diseases.

[0026] In the context of the invention, the term moxifloxacin is to be understood as a moxifloxacin base or its pharmaceutically acceptable salt, hydrate or solvate.

[0027] In our studies, IL6 measurement, which is one of the most important indicators of SASP in senescent cells, was performed and the increased SASP formation with doxorubicin was observed to be significantly suppressed due to the treatment of moxifloxacin. What we propose with this patent application is that moxifloxacin has a potential to be used as a new treatment approach in cases where adverse effects of SASP due to aging and cancer chemotherapy are observed.

[0028] The present invention encompasses a pharmaceutical composition comprising Moxifloxacin or its pharmaceutically acceptable salt, hydrate and solvate for use in inhibiting the secretory activity of senescent cells.

[0029] The composition of the invention is preferably Moxifloxacin hydrochloride or Moxifloxacin hydrochloride monohydrate. Said compositions may be administered orally, or as an intravenous infusion. When administered orally, the composition is preferably in a tablet form. When administered as an intravenous infusion, the composition is preferably in the form of a sterile solution.

[0030] The compositions of the invention may preferably be administered simultaneously or sequentially with a chemotherapy agent.

[0031] Another embodiment of the invention comprises Moxifloxacin or its pharmaceutically acceptable salt, hydrate and solvate for use in inhibiting the secretory activity of senescent cells.

[0032] Said compound is preferably Moxifloxacin hydrochloride or Moxifloxacin hydrochloride monohydrate.

[0033] Moxifloxacin or its pharmaceutically acceptable salt or hydrate for use according to the invention may be administered simultaneously or sequentially with a chemotherapy agent.

[0034] Inhibition of the secretory activity of senescent cells by moxifloxacin has been demonstrated by in vitro studies in Figs. 1 and 2.

[0035] In Vitro Experiment Results Evaluating the Senomorphic Efficacy of Moxifloxacin

[0036] Senescence was induced in HeLa cell line by the treatment of 300 nM doxorubicin for 72 hours. Senescence induction was morphologically confirmed (Fig. 1). Then, 10 pM and 100 pM moxifloxacin were treated to the senescent cells. After 48 hours of drug incubation, the supernatant (secretome) containing the factors secreted from the cells was collected. In the obtained secretomes, IL-6 measurement, which is the marker of the secretory activity of the senescent cell, was performed (Fig. 2). Our data showed that the IL-6 secretion increased with doxorubicin was significantly suppressed in a concentration-dependent manner by the treatment of moxifloxacin. The results showed that SASP was suppressed by 30% with 10 pM moxifloxacin and 50% with 100 pM moxifloxacin. Advantages of the Invention

[0037] The use of moxifloxacin in the treatment of various pathological conditions due to both cancer and aging will contribute to the reduction of health expenses related to these diseases in addition to its therapeutic effect. In addition, it will be easier for cancer patients to increase their adherence to treatment.

[0038] On the other hand, moxifloxacin may be used as an experimental tool that causes suppression of SASP in studies evaluating the activity of SASP in addition to its use as an adjunct agent in the administration of chemotherapy in cancer patients and in the prevention of pathological conditions due to aging.

[0039] A drug containing moxifloxacin or its pharmaceutically acceptable salt, hydrate or solvate may be used to reduce or alleviate the side effects or pathological conditions observed in an elderly person. Physiological changes in elderly are an increased risk factor for various diseases. Knowing the physiological changes that occur in the elderly is extremely important to understand the diseases that occur in the elderly. Based on a comprehensive understanding of these changes, it may be possible to take appropriate steps to protect elderly against diseases such as respiratory, cardiovascular, gastrointestinal, neurological, endocrine, immune, musculoskeletal and urinary system diseases and to adequately manage these diseases as they occur.

[0040] Description of Figures

[0041] Fig. 1 Morphological images of cells

[0042] A. Control group

[0043] B. 100 pM Moxifloxacin

[0044] C. Senescent cell

[0045] D. Senescent Cell + 100 pM Moxifloxacin

[0046] Fig. 2 Concentration dependent effect of moxifloxacin on the secretory activity of senescent HeLa cells.

Claims

CLAIMS1 . A pharmaceutical composition comprising Moxifloxacin or its pharmaceutically acceptable salt, hydrate and solvate for use in inhibiting the secretory activity of senescent cells.

2. Use according to claim 1 , wherein the composition comprises Moxifloxacin hydrochloride.

3. Use according to any one of the preceding claims, wherein the composition contains Moxifloxacin hydrochloride monohydrate.

4. Use according to any one of the preceding claims, wherein the composition is administered orally.

5. Use according to claim 4, wherein the composition is in the form of a tablet.

6. Use according to any one of claims 1 -3, wherein the composition is administered as an intravenous infusion.

7. Use according to claim 6, wherein the composition is in the form of a sterile solution.

8. Use according to any one of the preceding claims, wherein the composition is administered simultaneously or sequentially with a chemotherapy agent.

9. Moxifloxacin or its pharmaceutically acceptable salt, hydrate and solvate for use in inhibiting the secretory activity of senescent cells.

10. Moxifloxacin hydrochloride for use according to claim 9.

11. Moxifloxacin hydrochloride monohydrate for use according to any one of claims 9-10.

12. Use according to any one of the claims 9- 11 , wherein the composition is administered simultaneously or sequentially with a chemotherapy agent.

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