Rashed, S. | bioRxiv Science

bioRxiv2022

Polo-like kinase-1 Inhibitors and the Antiandrogen Abiraterone Synergistically Disrupt Mitosis and Kill Cancer Cells of Disparate Origin Independently of Androgen Receptor Signaling

Abiraterone, a standard treatment for metastatic castrate-resistant prostate cancer (mCRPC), slows disease progression by abrogating androgen synthesis and antagonizing the androgen receptor (AR). We report that inhibitors of the mitotic kinase Plk1, including the clinically active third-generation Plk1 inhibitor onvansertib, when co-administered with abiraterone, synergistically kill cancer cells from a wide variety of tumor types in an androgen-independent manner, both in vitro and in vivo. Abiraterone treatment alone results in defects in mitotic spindle orientation, failure of complete chromosome condensation, and upregulation of mitosis and mitotic-spindle related gene sets independently of its effects on AR signaling. These effects, while mild following abiraterone monotherapy, result in profound sensitization to the anti-mitotic effects of Plk1 inhibition, leading to spindle assembly checkpoint-dependent mitotic cell death and entosis. In a murine PDX model of mCRPC, combined onvansertib and abiraterone resulted in enhanced mitotic arrest and dramatic inhibition of tumor cell growth compared to either agent alone. STATEMENT OF SIGNIFICANCEA phase 2 clinical trial is underway (NCT03414034) testing combined Plk1 inhibitor onvansertib and abiraterone in mCRPC patients with nascent abiraterone resistance. Our work establishes a mechanistic basis for that trial and indicates that combined abiraterone and onvansertib co-treatment may have broad utility for cancer treatment beyond mCRPC.

cancer biology↗

bioRxiv2018

A novel green approach for treatment of immature Schistosomiasis Mansoni infection in mice; Arabic gum (Acacia Senegal) antischistosomal properties

Schistosomiasis is one of the most socioeconomically exhausting parasitic infection in tropical and subtropical areas. Praziquantel (PZQ), the only common schistosocidal drug in use, is not efficient enough for treatment of immature infection. Arabic gum (AG) is a complex polysaccharide acts as anti-oxidant which modulates the inflammatory and/or immunological processes. This study explores for the first time, the antischistosomal properties of AG in mice infected with the immature stage of Schistosoma mansoni. Mice were divided into four groups: control group (infected non-treated), AG treated group, PZQ treated group, and AG+PZQ treated group. Oral administration of AG in a dose of 1gm/kg body weight, daily for 3 consecutive weeks post-infection (p.i.) resulted in a statistically significant lower worm burden in both AG group and AG+PZQ group compared to PZQ and control groups. AG+PZQ group always showed the best performance when compared with other groups regarding tissue egg load and oogram pattern. AG, both alone and in combination with PZQ, decreased the number, diameter; increased the cellularity and the number of degenerated Schistosoma eggs inside granulomas. Results obtained by this work elucidated a promising AG bioactivity against S. mansoni immature stages and provided a platform for subsequent experimental studies to illuminate the academia more about this novel and \"green\" antischistosomal agent.\n\nAuthor summarySchistosomiasis is a major public health threat in many parts of the world, it affects more than 240 million people in more than 70 countries and almost 800 million people are at risk of acquiring this disease. Serious consequences and disabilities might result from untreated schistosomiasis such as hepatosplenic fibrosis with portal hypertension, gastrointestinal hemorrhage and death.\n\nSchistosomiasis control is focused on periodic treatment with praziquantel (PZQ). However, PZQ has only moderate action against young developing stages of schistosomula. Recently, resistance has emerged to PZQ. Therefore, chemotherapy alone is unlikely to reduce infection levels of schistosomiasis. Several practical approaches have been suggested to augment treatment programs. Of course, the development of a complementary treatment would contribute enormously to the reduction of schistosomiasis. Recently, natural products have been popular and attracted most of the attention as it could offer new effective therapy against schistosomiasis. Arabic gum (AG) is an edible, dried sticky exudate from Acacia Senegal, which is used in this study to assess the AG antischistosomal properties. Our study revealed that AG has an excellent statistically significant effect against immature murine schistosomiasis, both alone and in combination with PZQ. This approach may point to novel targets for treatment of schistosomiasis.

microbiology↗