Mmm, there is definitely a mismatch between in vitro and in vivo efficacy between the drugs, but Bisantrene is targeting a much more influential protein. Using the human equivalence dose calculations gives me the following for a standardised 60kg human:
Bisantrene = 15 mg/m2 Carfilzomib = 3.7 mg/m2
The dose for Carfilzomib given to the mice is roughly 5-7x less than what is given to humans. So, you are correct in saying that a synergistic combination at doses below what can be detected on their own is valid. But I thought I would showcase the vastness of targeting the FTO protein regardless. The crazy thing about FTO in cancer is that we probably know 2-5% of what there is to know, and we already know so much.
Simple Summary for the Below Information
FTO is the owner of the club (cancer) and recruits bouncers (efflux transporters) that kick roudy people out. When FTO is becomes too powerful, it recruits many bouncers. When you remove or inhibit FTO, you decrease the number of bouncers in the club, and hoodlums like @Kron00 can linger and cause havoc.
MM.1S Cell Line Expresses Efflux Transporters that Confers Carfilzomib Resistance
ABC transporters (efflux transporters), specifically ABCG2 and ABCC5, play a significant role in the resistance of MM.1S multiple myeloma cell lines to the chemotherapeutic agent carfilzomib. Resistin enhances the expression of efflux transporters ABCC5 and ABCG2, which in turn increases the efflux of proteasome inhibitors, bortezomib and carfilzomib, from MM.1S multiple myeloma cells. This leads to reduced drug accumulation inside the cells and contributes to chemotherapy resistance.
The following study found that multiple myeloma (MM) cells resist the cancer drug carfilzomib. This resistance is due to high levels of a protein called P-glycoprotein (ABCB1), an efflux transporter. When MM cells develop resistance, they show more of this transporter. The study also discovered that adding another drug, vismodegib, can help overcome this resistance by decreasing the efflux transporters.
The Regulatory Role of FTO in Expression of Efflux Transporters
The role of FTO, which can be further classified as dysregulated m6A levels, in cancer is in its infancy of being understood. Motivated by the recent findings, I decided to see whether FTO influenced the expression of drug transporters. Recent studies have demonstrated the pivotal role of FTO in drug resistance, particularly in the context of efflux transporter expression in cancer cells. FTO modulates the methylation status of RNA, impacting the stability and expression of numerous genes associated with cancer progression and drug resistance. For instance, in non-small cell lung cancer (NSCLC), FTO has been shown to regulate the expression of multidrug resistance proteins such as ABCC10 and ABCG2 via m6A demethylation mechanisms. Knockdown of FTO in gefitinib-resistant (GR) cell lines resulted in decreased expression of these transporters and increased sensitivity to gefitinib, indicating a direct link between FTO activity and efflux transporter-mediated drug resistance. Another study confirmed the FTO inhibitor Meclofenamic acid significantly downregulated the efflux proteins BCRP and MRP7 increasing intra-tumoral gefitinib accumulation and resensitizing gefitinib-resistant NSCLC to gefitinib. FTO was also shown to play a role in the glutamine transporterSLC1A5, where FTO knockdown decreased the expression of SCA1A5 reducing intracellular glutamine uptake needed for ccRCC growth and survival.
In acute myeloid leukemia (AML), FTO is highly expressed in multidrug-resistant cells, contributing to chemotherapy failure. The expression of efflux transporters MRP1 and MRP2 were highly expressed among 255 AML patients demonstrating a low m6A score (FTO overexpression). The low m6A score was associated with prognostic results and antitumor immuneresponses in acute myeloid leukemia. Further studies revealed that inhibition of FTO by compounds like Rhein leads to the suppression of cell proliferation and migration, induction of apoptosis, and increased sensitivity to chemotherapeutic agents such as azacitidine. This inhibition is mediated through the downregulation of efflux transporters and key signaling pathways like AKT/mTOR. The reduction in FTO activity leads to increased m6A levels in target mRNAs, reducing their stability and translation, thereby reversing drug resistance. These findings suggest that targeting FTO could be a promising strategy to overcome drug resistance in AML by modulating the expression of efflux transporters and enhancing the efficacy of existing chemotherapy regimens.
Decitabine Resistance Influenced by Efflux Transporter Expression
Recent studies have focused on understanding the role of efflux transporter expression and drug resistance in the context of decitabine (DAC) treatment. In one study, DAC resistance in HCT116 colorectal cancer (CRC) cells was established through long-term exposure to increasing concentrations of DAC. The results demonstrated a significant increase in the IC50 value of DAC, indicating acquired resistance. This resistance was associated with changes in the expression of key enzymes involved in drug metabolism, specifically increased levels of cytidine deaminase (CDA) and decreased levels of deoxycytidine kinase (dCK). These alterations were believed to contribute to the resistance observed, as both CDA and dCK are crucial in the metabolic pathways of DAC and gemcitabine (Gem).
Another study examined the impact of DAC on the expression of the ABCB1 gene and its product, P-glycoprotein (P-gp), which are known to mediate multidrug resistance (MDR). The study found that DAC treatment reduced the expression of ABCB1 mRNA and P-gp in drug-resistant hematopoietic cell lines, specifically MOLT4/DNR and Jurkat/DOX cells. This reduction in efflux transporter expression was accompanied by increased sensitivity to anticancer drugs such as daunorubicin and doxorubicin. The findings suggest that DAC's ability to modulate DNA methylation can reverse MDR phenotypes by decreasing the expression of efflux transporters like P-gp, thereby restoring drug sensitivity in resistant cell lines.
The role of FTO in regulating efflux transporter expression is an emerging area of research. Evidence suggests that inhibiting FTO with Bisantrene can decrease efflux transporter expression, increasing intra-tumoral carfilzomib accumulation and enhancing anti-cancer synergy. If FTO inhibition similarly affects Decitabine accumulation in humans, the in vitro solid tumor combination of Bisantrene and Decitabine could potentially translate into effective treatments in humans expanding the TAM for Inqovi 10-fold. This is an exciting time, as we are on the brink of discovering the full potential of this drug in cancer therapy. Chemoresistance associated with FTO was linked to 16 drug classes in early 2022, and this number has now grown to 25. Bisantrene stands as a first-in-class drug in a multi-billion-dollar industry with no current clinical or commercial competitors.
RAC Price at posting:
$1.79 Sentiment: Buy Disclosure: Held
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