Acute T-cell lymphoblastic leukemia (T-ALL) is an aggressive blood tumor arising from early T-cell progenitors. Notch signalling is recognized as one of the key oncogenes responsible for the pathogenesis of T-ALL and its resistance to common chemotherapeutic agents. Several approaches to target Notch have been investigated and have proved their antiproliferative effects in T-ALL, however, their clinical implication is restricted by low efficacy and severe adverse effects, moreover, their combination with common antileukemic drugs does not look unequivocally beneficial. Since the prognosis of patients who experience relapse after the front-line therapy remains unfavourable, it becomes important to unveil the mechanisms underlying T-ALL chemoresistance and to discover new pharmacological agents or novel drug combinations with high potential for further clinical development. Previously, we identified a chalcone molecule, namely Compound 8 (C8), derived from naturally occurring chalcone butein, as an inhibitor of Notch signalling and cell growth in several Notch-dependent T-ALL cell lines supported by halted cell cycle progression and induction of apoptosis without affecting non-malignant Notch-expressing keratinocytes HaCaT. The proposed research aims to further investigate C8 as a drug candidate for T-ALL treatment by testing it in combination with pharmacological agents used for the treatment of T-ALL on several human T-ALL cell lines in order to identify the pros and cons of its alliances with different chemotherapeutic drugs in terms of synergy/additivity/antagonism and/or overcoming T-ALL resistance to antileukemic drugs. The evaluation of C8 effects in combination with conventional chemotherapy agents represents a necessary step for its development as an antileukemic candidate drug and would provide the basis for the design of novel and more efficient combinatorial treatment in T-ALL.
The discovery of new anti-cancer drug candidates is undoubtedly relevant, however, even optimal antitumoral properties of a chosen molecule in a preclinical setting would not allow to test it as a single agent for the treatment of humans. Therefore, it becomes quite important to evaluate a selected agent not only alone but also to make the best out of it together with its future allies - conventional chemotherapeutic agents. From the pharmacological point of view, it may help to design drug combinations considering the drug reciprocal interactions in terms of additivity, synergism, and antagonism thus adjusting the dose ratio and the administration regimen [1]. Apart from being more rational, this approach looks economically beneficial, since it would predict or help to avoid some undesirable reactions that could block drug candidate development in the advanced clinical setting [2-3].
The knowledge on the combination between known Notch inhibitors and chemotherapeutic drugs in T-ALL is limited to few studies and appears to be controversial [4-8]. Moreover, the interaction between chemotherapy drugs and chalcones has not been studied enough with quite restricted evidence available supporting chalcone addition to vincristine and cytarabine, however, the chemical structure of these molecules shared quite few common features with our lead compound [9-11]. In this perspective, the evaluation of C8 effects in combination with conventional chemotherapy agents represents not only a necessary step for its development as an antileukemic candidate drug, but it will also provide additional evidence of pharmacological interaction between Notch inhibitors, plant-derived compounds and common anticancer drugs used for T-ALL treatment and will contribute to the characterization of T-ALL chemoresistance patterns. Our preliminary results support the feasibility of the project indicating C8 synergism with vincristine and dexamethasone and antagonism with doxorubicin. However, they should be confirmed in additional cell lines, supported by the identification of the underlying molecular mechanism, and completed with the data on other antileukemic drugs in order to create a more comprehensive picture. Nonetheless, in case of antagonistic incompatibility of C8 with all tested antileukemic drugs additional chalcone derivatives from our library will be evaluated.
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