Comprehensive review on how platinum- and taxane-based chemotherapy of ovarian cancer affects biology of normal cells

Abstract

One of the most neglected aspects of chemotherapy are changes, and possible consequences of these changes, that occur in normal somatic cells. In this review, we summarize effects of selected drugs used to treat ovarian cancer (platin derivatives—cisplatin and carboplatin; and taxanes—paclitaxel and docetaxel) on cellular metabolism, acquisition of reactive stroma features, cellular senescence, inflammatory reactions, apoptosis, autophagy, mitophagy, oxidative stress, DNA damage, and angiogenesis in various types of normal cells, including fibroblasts, epithelial cells, endothelial cells, and neurons. The activity of these drugs against the normal cells is presented from a broader perspective of their desirable anti-tumoral effects.

Cellular Responses to Platinum-Based Anticancer Drugs and UVC: Role of p53 and Implications for Cancer Therapy

“…Cisplatin is widely used in the treatment of many solid cancers, including those of the lung, cervix, testes, ovary, breast, bladder, head and neck, esophagus and brain, as well as mesothelioma, neuroblastoma, sarcomas, and hematological cancers such as leukemias and lymphomas [4][5][6][7]. Almost all of the major reviews on this topic (e.g., [4][5][6][7][8][9][10]) concur that the therapeutic effects of cisplatin against solid tumour-derived cells are primarily a result drug-induced DNA damage, although non-DNA targets may also contribute (e.g., [5,7]). Cisplatin-induced damage to DNA includes mono-adducts, intra-strand crosslinks and interstrand crosslinks.…”

Mesenchymal Stem Cells As Guideposts for Nanoparticle-Mediated Targeted Drug Delivery in Ovarian Cancer

“…When we compared paclitaxel delivery using nanoparticles (both with or without the addition of MSCs) to saline controls we found no changes in apoptosis or angiogenesis markers in the tumors, while there was a slight decrease in the proliferation marker Ki-67 and an increase in necrosis ( Table 2). This is somewhat surprising, as paclitaxel is known to trigger apoptosis in ovarian cancer due to its capacity to decrease mitochondrial membrane potential [59]. We did not detect any noticeable differences in the markers or necrosis score, when comparing free nanoparticles to nanoparticles, combined with MSCs, suggesting our two-step delivery method does not affect paclitaxel's mechanism of cell cytotoxicity when delivered using nanoparticles.…”

“…Paclitaxel's primary mechanism of cytotoxicity is attributed to its ability to bind tubulin and stabilize microtubules, resulting in mitotic arrest and subsequent cell death [58,59]. However, there is evidence that paclitaxel may employ alternative methods of cell-killing, independent of mitotic arrest [60].…”

Cancer epithelia-derived mitochondrial DNA is a targetable initiator of a paracrine signaling loop that confers taxane resistance

“…Incidentally, when lymphocytes secrete mtDNA in response to viral infection, it is not associated with cell death (55). However, since mitophagy is a documented process associated with taxane therapy, only fragments of the mitochondrial genome would likely be found in the media or circulation (56) with high susceptibility for further degradation. CAF reciprocated the PCa-derived mtDNA signal by the TLR9-C3 paracrine axis to trigger cell proliferation in PCa cells in the context of docetaxel (Fig.…”