Sonodynamic therapy is a potential cancer treatment modality that has been gaining support due to its effectiveness in both in vitro and in vivo studies. The therapeutic method combines ultrasonic irradiation with drugs known as sonosensitizers that amplify its ability to inflict preferential damage on malignant cells. This is based on the idea that ultrasonic waves have the ability to exhibit profound physical and chemical changes on cellular structure. The mechanisms by which ultrasound (US) disrupts cellular functioning can be further amplified when sonosensitizers are applied. Combining multiple sonosensitizers with US to create a substantial synergistic effect could be an effective method for destroying tumorigenic growths, while decreasing the likelihood of drug resistance.

Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent, which has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient's quality of life but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify a priori those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin-induced ototoxicity, neurotoxicity, and nephrotoxicity. Traditional genome-wide association studies have identified single-nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy, with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression, and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities and currently available means to prevent or treat their occurrence.

Although cytoskeletal-directed agents have been a mainstay in chemotherapeutic protocols due to their ability to readily interfere with the rapid mitotic progression of neoplastic cells, they are all microtubule-based drugs, and there has yet to be any microfilament- or intermediate filament-directed agents approved for clinical use. There are many inherent differences between the cytoskeletal networks of malignant and normal cells, providing an ideal target to attain preferential damage. Further, numerous microfilament-directed agents, and an intermediate filament-directed agent of particular interest (withaferin A) have demonstrated in vitro and in vivo efficacy, suggesting that cytoskeletal filaments may be exploited to supplement chemotherapeutic approaches currently used in the clinical setting. Therefore, this review is intended to expose academics and clinicians to the tremendous variety of cytoskeletal filament-directed agents that are currently available for further chemotherapeutic evaluation. The mechanisms by which microfilament directed- and intermediate filament-directed agents damage malignant cells are discussed in detail in order to establish how the drugs can be used in combination with each other, or with currently approved chemotherapeutic agents to generate a substantial synergistic attack, potentially establishing a new paradigm of chemotherapeutic agents.

Although the amount of progress cancer therapy has made in recent years is commendable, considerable limitations still remain. Most agents preferentially target rapidly proliferating cells, thereby destroying tumorigenic growths. Unfortunately, there are many labile cells in the patient that are also rapidly dividing, ultimately perpetuating significant side effects, including immunosuppression. Cytochalasins are microfilament-directed agents most commonly known for their use in basic research to understand cytoskeletal mechanisms. However, such agents also exhibit profound anticancer activity, as indicated by numerous in vitro and in vivo studies. Cytochalasins appear to preferentially damage malignant cells, as shown by their minimal effects on normal epithelial and immune cells. Further, cytochalasins influence the end stages of mitosis, suggesting that such agents could be combined with microtubule-directed agents to elicit a profound synergistic effect on malignant cells. Therefore, it is likely that cytochalasins could be used to supplement current chemotherapeutic measures to improve efficacy rates, as well as decrease the prevalence of drug resistance in the clinical setting.

Purpose: Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy. Experimental Design: TCS (n ¼ 762) were dichotomized to cases (moderate/severe tinnitus; n ¼ 154) and controls (none; n ¼ 608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in genome-wide association study (GWAS) following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed. Results: Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (P ¼ 0.007) and cumulative cisplatin dose (P ¼ 0.007). CisIT prevalence was not significantly greater in 400 mg/m 2-treated TCS compared with 300 (P ¼ 0.41), but doses >400 mg/m 2 (median 580, range 402-828) increased risk by 2.61-fold (P < 0.0001). CisIT cases had worse hearing at each frequency (0.25-12 kHz, P < 0.0001), and reported more vertigo (OR ¼ 6.47; P < 0.0001) and problems hearing in a crowd (OR ¼ 8.22; P < 0.0001) than controls. Cases reported poorer health (P < 0.0001) and greater psychotropic medication use (OR ¼ 2.4; P ¼ 0.003). GWAS suggested a variant near OTOS (rs7606353, P ¼ 2 Â 10 À6) and OTOS eQTLs were significantly enriched independently of that SNP (P ¼ 0.018). OTOS overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q ¼ 0.007). Conclusions: CisIT associated with several neurootological symptoms, increased use of psychotropic medication, and poorer health. OTOS, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells.

SummaryBackground Despite inherent differences between the cytoskeletal networks of malignant and normal cells, and the clinical antineoplastic activity of microtubule-directed agents, there has yet to be a microfilament-directed agent approved for clinical use. One of the most studied microfilament-directed agents has been cytochalasin B, a mycogenic toxin known to disrupt the formation of actin polymers. Therefore, this study sought to expand on our previous work with the microfilament-directed agent, along with other less studied cytochalasin congeners. Materials and Methods We determined whether cytochalasin B exerted significant cytotoxic effects in vitro on adherent M109 lung carcinoma and B16BL6 and B16F10 murine melanomas, or on suspension P388/ADR murine leukemia cells. We also examined whether cytochalasin B, its reduced congener 21, 22-dihydrocytochalasin B (DiHCB), or cytochalasin D could synergize with doxorubicin (ADR) against ADR-resistant P388/ADR leukemia cells, and produce significant cytotoxicity in vitro. For in vivo characterization, cytochalasins B and D were administered intraperitoneally (i.p.) to Balb/c mice challenged with drug sensitive P388-S or multidrug resistant P388/ADR leukemias. Results Cytochalasin B demonstrated higher cytotoxicity against adherent lung carcinoma and melanoma cells than against suspension P388/ADR leukemia cells, as assessed by comparative effects on cell growth, and IC50 and IC80 values. Isobolographic analysis indicated that both cytochalasin B and DiHCB demonstrate considerable drug synergy with ADR against ADR-resistant P388/ADR leukemia, while cytochalasin D exhibits only additivity with ADR against the same cell line. In vivo, cytochalasins B and D substantially increased the life expectancy of mice challenged with P388/S and P388/ADR leukemias, and in some cases, produced long-term survival. Conclusion Taken together, it appears that cytochalasins have unique antineoplastic activity that could potentiate a novel class of chemotherapeutic agents.

Despite recent advances in precision medicine, many molecular-based antineoplastic agents do not potentiate sustainable long term remissions, warranting the investigation of novel therapeutic strategies. Heat shock protein 90 (Hsp90) is a molecular chaperone that not only has oncogenic properties, but also has distinct expression profiles in malignant and normal cells, providing a rational strategy to attain preferential damage. Prior attempts to target Hsp90 with natural product-based compounds have been hampered by their associated off target toxicities, suggesting that novel, fully synthetic inhibitors may be required to achieve the specificity necessary for therapeutic efficacy. Therefore, this review highlights the antineoplastic potential of PU-H71 (8-[(6-iodo-1,3-benzodioxol-5-yl)sulfanyl]-9-[3-(propan-2-ylamino)propyl]purin-6-amine), a novel purine based analog that has shown efficacy in many preclinical models of malignancy, and is now under clinical examination. In addition, the review suggests potential concomitant therapeutic approaches that may be particularly beneficial to molecular-based, as well as traditional cytotoxic cancer chemotherapy.

Nearly all cancers are linked by the inexorable phenotype of metastasis as malignant growths have the capability to spread from their place of origin to distant sites throughout the body. While different cancers may have various propensities to migrate towards specific locations, they are all linked by this unifying principal. Unlike most neoplasms, leukaemia has inherent cell motility as leukocytes are required to move throughout the vascular system, suggesting that no mutations are required for anchorage independent growth. As such, it seems likely that leukaemias are inherently metastatic, endowed with the deadliest phenotype of cancer simply due to cell of origin. This article presents the biology of metastasis development and how leukaemia cells are inherently provided these phenotypic characteristics. It is then proposed how clinicians may be able to exploit the motility of leukaemia and metastatic emboli of other cancer types through an approach known as sonodynamic therapy (SDT), a treatment modality that combines chemotherapeutic agents with ultrasound to preferentially damage malignant cells. As experimental evidence has indicated, SDT is a promising therapeutic approach in need of clinical testing for further validation.