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Singh, Harshabad

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Singh

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Harshabad

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Singh, Harshabad

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2014 - 201912020 - 20251

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Author's Publications: search.filters.isAuthorOfPublication.d4f4a36b-a22b-4040-ad85-3dc75a9c9346

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    The glutathione synthesis inhibitor buthionine sulfoximine synergistically enhanced melphalan activity against preclinical models of multiple myeloma
    (Nature Publishing Group, 2014) Tagde, Ashujit; Singh, Harshabad; Kang, M H; Reynolds, C P
    Melphalan (L-PAM) has been an integral part of multiple myeloma (MM) treatment as a conditioning regimen before stem cell transplant (SCT). After initial response, most treated patients experience relapse with an aggressive phenotype. Increased glutathione (GSH) in MM may mediate resistance to L-PAM. We demonstrated that the GSH synthesis inhibitor buthionine sulfoximine (BSO) synergistically enhanced L-PAM activity (inducing 2–4 logs of cell kill) against nine MM cell lines (also in the presence of marrow stroma or cytokines) and in seven primary MM samples (combination indices <1.0). In MM cell lines, BSO significantly (P<0.05) depleted GSH, increased L-PAM-induced single-strand DNA breaks, mitochondrial depolarization, caspase cleavage and apoptosis. L-PAM depleted GSH, but GSH rapidly recovered in a L-PAM-resistant MM cell line unless also treated with BSO. Treatment with N-acetylcysteine antagonized BSO+L-PAM cytotoxicity without increasing GSH. In human MM xenografted into beige-nude-xid mice, BSO significantly depleted MM intracellular GSH and significantly increased apoptosis compared with L-PAM alone. BSO+L-PAM achieved complete responses (CRs) in three MM xenograft models including maintained CRs >100 days, and significantly increased the median event-free survival relative to L-PAM alone. Combining BSO with L-PAM warrants clinical testing in advanced MM.
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    Crypt density and recruited enhancers underlie intestinal tumour initiation
    (Springer Science and Business Media LLC, 2025-01-08) Gaynor, Liam; Singh, Harshabad; Tie, Guodong; Badarinath, Krithika; Madha, Shariq; Mancini, Andrew; Bhattacharya, Swarnabh; Hoshino, Mikio; de Sauvage, Frederic J.; Murata, Kazutaka; Jadhav, Unmesh; Shivdasani, Ramesh; tie, guodong
    Oncogenic mutations that drive colorectal cancer can be present in healthy intestines for long periods without overt consequence. Mutation of Adenomatous polyposis coli (Apc), the most common initiating event in conventional adenomas, activates Wnt signalling, hence conferring fitness on mutant intestinal stem cells (ISCs). Apc mutations may occur in ISCs that arose by routine self-renewal or by dedifferentiation of their progeny. Although ISCs of these different origins are fundamentally similar, it is unclear if both generate tumours equally well in uninjured intestines. Also unknown is whether cis-regulatory elements are substantively modulated upon Wnt hyperactivation or as a feature of subsequent tumours. Here, we show in two mouse models that adenomas are not an obligatory outcome of Apc deletion in either ISC source but require proximity of mutant intestinal crypts. Reduced crypt density abrogates, and aggregation of mutant colonic crypts augments, adenoma formation. Moreover, adenoma-resident ISCs open chromatin at thousands of enhancers that are inaccessible in Apc-null ISCs not associated with adenomas. These cis-elements explain adenoma-selective gene activity and persist, with little further expansion of the repertoire, as other oncogenic mutations accumulate. Thus, cooperativity between neighbouring mutant crypts and new accessibility at specific enhancers are key steps early in intestinal tumourigenesis.