Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

Abstract

Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects.

Roles of p53 and Caspases in Induction of Apoptosis in MCF-7 Breast Cancer Cells Treated with a Methanolic Extract of Nigella Sativa Seeds

“…The mechanism of action of many anticancer drugs is based on their ability to induce apoptosis (Motomura et al, 2008;Florea and Busselberg, 2011). However, unfavorable side effects and the resistance to many anticancer agents have become serious problems (Sonis et al, 2011).…”

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…Cisplatin treatment can induce several types of adverse effects including GI disorders, kidney injury, neurotoxicity, hepatotoxicity, and cardiotoxicity (Kitamura 2008; Pabla and Dong 2008; Florea and Büsselberg 2011). Many investigations have been performed to decipher the mechanisms of cisplatin‐induced acute kidney injury because this frequent adverse effect limits the use of cisplatin in cancer therapy (Kitamura 2008; Pabla and Dong 2008).…”

Pharmaceutical properties of supramolecular assembly of co-loaded cardanol/triazole-halloysite systems

“…Over 80% of liver cancer patients are diagnosed with hepatocellular carcinoma, which is resistant to most conventional chemotherapeutic agents (Wilson et al, 2012). Moreover, the use of chemoprevention agents is typically associated with side effects that lead to the destruction of normal tissues, such as those of the digestive, hematopoietic and nervous systems (Meyskens and Gerner, 1999;Suzuki et al, 2008;Florea and Büsselberg, 2011). The development of drugs that specifically target tumor cells, but not normal cells, represents a common goal.…”