The effects of chemotherapeutic or antiretroviral drugs on mitochondrial function

Abstract

Chemotherapeutic drugs such as anthracyclines and antiretroviral drugs such as nucleoside reverse transcriptase inhibitors (NRTIs) have been in use for decades and are highly effective drugs. Unfortunately, drugs that affect tumor or viral DNA can also affect mitochondrial DNA, leading to deleterious side effects such as cardiomyopathy, metabolic disorders, or peripheral neuropathy. There is a dearth of information as to how these drugs affect mitochondrial function in certain populations and how much drug exposure must occur before these changes manifest (short-term versus life long treatment). In this dissertation, we examined the long-term effects of treatment with an anthracycline, doxorubicin (DOX), and an adjuvant therapy, dexrazoxane (DEX), on mitochondrial function in childhood survivors of acute lymphoblastic leukemia (Chapter 2). We also examined the long-term mitochondrial effects of combination antiretroviral treatment (cART) in perinatally HIV-infected adolescent populations with and without insulin resistance (Chapter 3). Additionally, we performed a cross-sectional analysis on adult populations from Thailand who were HIV-infected and cART naïve, HIV-infected with an NRTI induced symptomatic peripheral neuropathy (PN), or HIV negative on mitochondrial parameters as well as measures of epidermal nerve fiber densities (ENFD), antioxidant levels, and oxidative stress. Finally, we performed a longitudinal analysis of the HIV-infected, drug naïve group on measures of ENFD, antioxidant levels, and oxidative stress at three time points: before cART treatment, during treatment with a stavudine (d4T) based regimen, and after switching to a zidovudine (ZDV) based regimen (Chapter 4). We hypothesized that in each study drug treatment would affect mitochondrial DNA numbers and oxidative phosphorylation enzyme activities. In the final study, we also hypothesized that the group with PN would have lower ENFD, and more mitochondrial dysfunction and oxidative stress than the groups without PN. Finally, we hypothesized that treatment with the mitochondrially toxic d4T would induce more ENFD loss, mitochondrial dysfunction, and oxidative stress than treatment with the less mitochondrially toxic ZDV in the HIV-infected group without PN. We observed across these three studies that drugs that affect tumor cell or viral DNA replication can alter mitochondrial function either through alterations to the DNA, observed as lower copy numbers per cell, or through disturbances in the oxidative phosphorylation system, measured as changes in complex I or IV enzyme activities. We also found in the final study those with d4T-indcued PN have greater mitochondrial dysfunction and oxidative stress than those who are HIV-infected and drug naïve. Finally, we determined that shortterm d4T treatment induces similar mitochondrial alterations and oxidative stress as those seen in the HIV infected group with PN, which can be ameliorated through a drug regimen switch to ZDV. Taken together, the results from these studies indicate that these drugs, while very effective, are inducing systemic mitochondrial changes and research in this area should continue in order to determine the full extent of the mitochondrial alterations. This information could one day lead to equally effective treatments that are more mitochondrial friendly, improving patient quality of life.