Chemotherapy drugs are powerful cellular toxins that kill rapidly dividing cancer cells. Unfortunately, normal cells and tissues also suffer from this, especially those in rapid renewal (e.g. bone marrow, skin AND inner mucosae). Therefore, scientists continue to look for new ways of chemotherapy that could make the effects of chemotherapeutic agents more selective. Biochemists from RUDN and IBMC have found a way to protect healthy leukocytes during leukemia chemotherapy. Small nitrogen-containing polyamine molecules give the necessary protection. Polyamines are nitrogen-containing compounds found in almost all living cells; examples are putrescine and spermidine. In addition, they have an antioxidant effect and promote DNA repair. Various polyamines are involved in cell growth (proliferation) and some of them also in brain function (like agmatine). Moreover, the more actively the cells grow, the more polyamines they consume and/or secrete.
Therefore, the concentration of polyamines in cancer cells is much higher than in healthy tissues. There is an advantageous glitch in all this: they are synthesized by almost all living cells, but only in normal lymphocytes they exhibit protective properties. Biochemists have shown that polyamines “protect” healthy human T -lymphocytes, but not cancer cells. Thus, if you first treat lymphocytes with polyamines, and then with a chemotherapeutic drug, then the chances of survival increase for healthy cells. In this case, cancer-affected lymphocytes (like those of lymphoma) are not protected. To test their hypothesis scientists used healthy lymphocytes as well as the K562 and Jurkat cell lines. The first corresponds to myeloid leukemia (AML), the second to lymphoblastic leukemia (ALL). Both diseases affect white blood cells called lymphocytes. The cells were exposed to one of three common chemotherapy drugs (cisplatin, doxorubicin or irinotecan). These drugs have in common the ability to induce DNA damage either directly or indirectly.
Some of the cells were previously treated with polyamines. The survival of healthy cells increased several times – for example, from 25% to 110% for lymphocytes treated with polyamine spermidine and then cisplatin. In cancer cells, the survival rate changed by only a few percentage. The reason for this action was the ability of polyamines to activate the synthesis of the protein RAD51A, a protein involved in the DNA repair system in normal, but not malignant, lymphocytes. Among the Rad proteins (A to D), only the isoform A was affected. It is ironic since among the early attempts to fight cancer there was the rationale to interfere with polyamine biosynthesis. One drug tested originally was difluoromethyl-ornitine, a suicide inhibitor of ornithine decarboxylase (ODC), the rate-limiting enzyme for polyamine production. However, it never officially entered chemotherapy and it was re-routed to treat Pneumocystis pneumonia and sleeping sickness infection.
Another polyamine synthesis inhibitor, mitoguazone, instead has found application for refractory prostate cancer while another (SAM486A) underwent clinical trials for Hodgkin lymphoma and melanoma. Polyamines, neverthelss, have roles in normal immune cell function and are needed for T cell proliferation and differentiation. Thus, a chemotherapeutic strategy against polyamines may have a negative effect on normal immune cells. This was never fully considered in the past. In this research, pretreatment of cells with polyamine putrescine led to a small and insignificant decrease in the proportion of dead Jurkat and K562 cell lines. However, pretreatment of normal CD4+ T cells with Putrescine resulted in significant prevention of cell death, and more than 80% of normal lymphocytes remained alive after the induction of apoptosis with cisplatin. The polyamine induced alternative splicing of the Rad51A mRNA and, according to researcher, is the first time such mechanism is shown in this context.
Although most polyamine-related anticancer strategies are aimed to decrease spermine and spermidine concentration in tumor cells, some cell types including leukemia cells remain anergic for polyamine at low doses. This promising fact, would makes possible the clinical evaluations of polyamines administration in combination with standard chemotherapy to spare normal immune cells from the chemo-toxicity.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in CLinical Biochemistry.
Scientific references
Gladilina YA et al. Internat J Mol Sci 2022; 23(3):1863.
Neborak EV et al. Molecules. 2022; 27(12):3872.
Nakkina SP et al. Int J Mol Sci. 2021; 22(24):13175.
Zhdanov DD et al. Biochimie. 2020; 174:34-43.
Dever TE, Ivanov IP. J Biol Chem. 2018; 293:18719.
Dott. Gianfrancesco Cormaci
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