Anticancer Drugs Paclitaxel, Carboplatin, Doxorubicin, and Cyclophosphamide Alter the Biophysical Characteristics of Red Blood Cells, In Vitro

SIMPLE SUMMARY: An important issue in cancer chemotherapy is minimizing its side effects. The extreme toxicity of chemotherapy drugs is due to their task of preventing the multiplication of cancer cells and causing cancer cell death. One of their most common undesirable side effects is anemia, which is caused by a decrease in the number of red blood cells (RBCs) circulating in blood, which in turn results in a lack of oxygen in tissues. The manifestation of anemia is associated not only with the inhibition of the hematopoietic function of bone marrow but also with direct damage to RBCs during the drugs’ infusion and circulation. Here, we investigated how frequently used chemotherapy drugs directly affect RBCs. Our results show that chemotherapeutic drugs, whose main task is to damage the DNA of cancer cells and prevent their division, have a noticeable toxic effect on RBCs. However, this effect is lower than the effect caused by drugs, which disrupt the dynamics of the cytoskeleton during cell division. Direct simulation of RBCs’ transport in microchannels of a microfluidic device was allowed to integrally assess the cells’ functionality and the capability of passing through microcapillaries where gas transport mainly occurs. We demonstrate that after exposure to drugs, regardless of their type, the number of damaged cells did not exceed 10%, which indicates the balance of the drugs’ therapeutic doses. Our data along with the developed research method could be used to work out an effective combination of chemotherapeutic drugs as well as to calculate the efficient therapeutic drug doses for cancer treatment to reduce anemia side effects. ABSTRACT: Red blood cells (RBCs) are the most numerous cells in the body and perform gas exchange between all tissues. During the infusion of cancer chemotherapeutic (CT) agents, blood cells are the first ones to encounter aggressive cytostatics. Erythrocyte dysfunction caused by direct cytotoxic damage might be a part of the problem of chemotherapy-induced anemia—one of the most frequent side effects. The aim of the current study is to evaluate the functional status of RBCs exposed to mono and combinations of widely used commercial pharmaceutical CT drugs with different action mechanisms: paclitaxel, carboplatin, cyclophosphamide, and doxorubicin, in vitro. Using laser diffraction, flow cytometry, and confocal microscopy, we show that paclitaxel, having a directed effect on cytoskeleton proteins, by itself and in combination with carboplatin, caused the most marked abnormalities—loss of control of volume regulation, resistance to osmotic load, and stomatocytosis. Direct simulations of RBCs’ microcirculation in microfluidic channels showed both the appearance of a subpopulation of cells with impaired velocity (slow damaged cells) and an increased number of cases of occlusions. In contrast to paclitaxel, such drugs as carboplatin, cyclophosphamide, and doxorubicin, whose main target in cancer cells is DNA, showed significantly less cytotoxicity to erythrocytes in short-term exposure. However, the combination of drugs had an additive effect. While the obtained results should be confirmed in in vivo models, one can envisioned that such data could be used for minimizing anemia side effects during cancer chemotherapy.