The potential use of natural products to negate hepatic, renal and neuronal toxicity induced by cancer therapeutics

Abstract

Different types of chemotherapeutics are used for cancer treatment. These drugs act on several signal pathways, lead to programmed cell death, and damage cancer cells. Although many specific mechanisms of action have been suggested for chemotherapeutics, there are still gaps in understanding their effects. They may affect different components of the cell, particularly proteins with specific functions, such as enzymes. Recently, targeted and immuno therapies were introduced for treatment of different cancers. However, many cancer patients still depend on traditional and well-known drugs. Doxorubicin and platinum-based drugs are among the most frequently used chemotherapeutics. They are highly cytotoxic for cancer cells, but they also act on healthy cells. Hence, it is crucial to understand the mechanisms involved in order to decrease their side effects. Natural products, many of which are also available over-the-counter, may be considered to decrease various cancer drug-induced side effects. This review focuses on the use of these compounds to overcome side effects of chemotherapeutics, primarily doxorubicin and cisplatin, in the liver, kidney, and neuronal systems.

Introduction

Cancer therapies that are routinely used for the treatment of different types of cancer vary in their potency. Challenges to successful treatment include not only limited efficacy, but also acquired drug resistance and organ toxicity. Organ toxicity is not limited to chemotherapy, it also occurs in targeted- and immuno-therapy. Since toxicity associated with chemotherapeutic agents is more prevalent, in this review we will focus on this critical barrier against effective treatment and deal with side effects of doxorubicin and cisplatin in the liver, kidney, and neuronal systems.

Doxorubicin (DOX) and platinum-based drugs are among the most abundantly used chemotherapeutics. However, although they are highly cytotoxic for cancer cells, their organ cytotoxicity limits their utilization. Therefore, it is critical to understand their mechanisms of action in order to decrease their side effects. Particularly the use of natural compounds to overcome the side effects of DOX and platinum-based drugs seems to be important. DOX is an anthracycline antibiotic and a broadspectrum antineoplastic agent. It is commonly used in tumor therapy of uterine, ovarian, breast, and lung cancers, solid tumors of childhood, Hodgkin and non-Hodgkin lymphomas, and soft tissue sarcomas as well as other cancer types [1], [2]. Following its discovery in Streptomyces peucetius in the early 1960s, DOX presented a considerable leap forward in the fight against cancer. DOX antitumor effects include mechanisms of DNA alteration and the production of free radicals [3], [4]. DOX interacts with DNA by intercalation and inhibition of macromolecular biosynthesis, which inhibits the progression of the enzyme topoisomerase II (Top2) [5], [6]. Top2 is the target of a wide array of anticancer agents: the anthracyclines (e.g., DOX, epirubicin, daunorubicin), the anthracenediones (e.g., mitoxantrone), and the podophyllotoxins (e.g., etoposide, teniposide) [7]. These agents act by blocking the process of replication, since the transient double strand breaks introduced by Top2 are crucial for replication, transcription, and chromosome segregation [8].

The clinical usefulness of DOX in long-term treatment is restricted, however, due to serious side effects. These can be acute and chronic, and include dose-dependent myocardial injury, which can lead to congestive heart failure [9]. In up to 26% of patients [10], DOX administration leads to arrhythmia or cardiomyopathy induced by the formation of reactive oxygen species and cytochrome c release from mitochondria [11]. It was also confirmed that therapeutic doses of DOX enhance lipid peroxidation in microsomes and mitochondria in the liver, especially in the presence of Fe³⁺ ions [12]. Even applications of a single dose of DOX have been proven to cause irreversible liver damage and an increase of the apoptotic processes in hepatic tissue [13], [14]. Other tissues like the kidneys, brain, and the skeletal muscle are also affected negatively by DOX [15].

Another group of chemotherapeutic agents for the treatment of cancer patients are platinum-based drugs. The anti-cancer activity of cis-diamminedichloroplatinum (II) (cis-[PtCl₂(NH₃)₂], CDDP, Cisplatin) was first reported in 1979, more than 40 years ago. Cisplatin and other platinum-based drugs have been routinely employed in the treatment of testicular, ovarian, cervical, bladder, and head/neck tumors [16]. The mechanism of action of cisplatin is based on the intrastrand cross-linking of the cis-Pt (NH₃)₂ unit to cellular DNA at two neighboring guanine bases [17] and the consequent induction of cellular apoptosis. While effective, the use of these platinum-based drugs (cisplatin, carboplatin, and oxaliplatin) is also limited by their severe, dose-limiting side effects. The dose-limiting side effect for cisplatin is nephrotoxicity, for carboplatin it is myelosuppression, and for oxaliplatin it is neurotoxicity. Patients are commonly co-prescribed nonchemotherapy-based drugs to treat these side effects, but with limited success [18].